HX641 27575 
RC1 56  .D34  A  practical  study  of 


RECAP 


Columtita  ®ntbergitj> 

in  tfje  Cttp  of  &*&  §9orfe 

COLLEGE  OF  PHYSICIANS 
AND   SURGEONS 


Reference  Library 

Given  by 


L 


Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/practicalstudyofOOdead 


"  There  are  more  mistakes  made  in  the  diagnosis  of  malaria 
with  the  microscope  than  perhaps  over  any  other  similar  study; 
on  the  other  hand,  if  properly  employed,  it  may  give  valuable 
information,  leading  perhaps  to  the  saving  of  life  "  (Manson). 


A    PRACTICAL    STUDY 


OF 


MALARIA 


BY 

WILLIAM    H.   DEADERICK,  M.  D. 

Member  of  the  Arkansas  Medical  Society,  American  Medical  Association,  and  American 

Society  of  Tropical  Medicine ;  Fellow  of  the  London  Society  of  Tropical 

Medicine  and    Hygiene;    Corresponding  Member  Societe   de 

Pathologie  Exotique   (Paris)  ;     President   of  the 

Tri-State   Medical  Society 


FULLY  ILLUSTRATED 


PHILADELPHIA    AND    LONDON 

W.    B.    SAUNDERS    COMPANY 
1909 


Copyright,  1909,  by  W.  B.  Saunders  Company 


PRINTED    IN    AMERICA 

PRESS    OF 

W.    B.    SAUNDERS    COMPANY 

PHILADELPHIA 


THESE  PAGES  ARE 

AFFECTIONATELY  DEDICATED 

TO   MY  MOTHER 


PREFACE 


While  there  is  a  number  of  good  books  on  malaria,  I  be- 
lieve there  is  a  place  for  a  work  written  by  one  engaged  entirely 
in  private  practice  largely  in  country  districts,  in  the  home  of  the 
severer  forms  of  the  disease. 

In  the  endeavor  to  make  the  work  as  practical  as  possible 
especial  attention  has  been  devoted  to  that  mystic  paramalarial 
syndrome,  hemoglobinuric  fever,  and  to  the  diagnosis  and  treat- 
ment of  malaria.  Prophylaxis  has  been  considered  in  the  light 
of  Ross'  epoch-making  discovery. 

The  parthenogenetic  cycle  of  the  parasite,  whose  significance 
was  first  recognized  by  Schaudinn,  and  which  affords  the  only 
rational  explanation  of  latency  and  relapse,  is  described  for  the 
first  time,  perhaps,  in  our  language. 

While  I  have  not  hesitated  to  draw  from  the  literature  for  the 
illustration  of  practical  points,  due  credit  is  given  in  the  reference 
portion.  I  am  especially  indebted  to  the  works  of  Ewing,  Dock, 
Barker,  Marchiafava  and  Bignami,  and  Kelsch  and  Kiener  for 
pathologic  data. 

I  am  grateful  to  my  wife  for  copying  the  manuscript  and  for 
assistance  in  reading  the  proof,  to  Mr.  W.  C.  Seckler  for  the 
photographic  work,  and  to  the  W.  B.  Saunders  Co.  for  courtesies 
throughout  the  publication  of  the  book. 

W.  H.  D. 

Marianna,  Arkansas,  October,  1909. 


CONTENTS 


CHAPTER  I  page 

Introduction 17 

History  of  Hemoglobinuria  Fever 23 


CHAPTER    II 

Geographic  Distribution 31 

Geographic  Distribution  of  Hemoglobinuric  Fever 34 


CHAPTER  III 

Etiology 38 

Dissemination  of  Malaria  by  Mosquitoes 69 

The  Malaria-bearing  Mosquitoes 74 

Classification  of  the  Mosquitoes  of  North  and  Middle  America   .    .  86 

The  Parasites  of  Malaria 112 

Pathogenesis 129 

Etiology  of  Pernicious  Malaria 140 

Etiology  of  Hemoglobinuric  Fever 153 


CHAPTER  IV 

Pathologic  Anatomy 174 

Acute  Malaria 175 

Chronic  Malaria 178 

Hemoglobinuric  Fever 180 


CHAPTER  V 

Clinical  History 184 

Acute  Malaria 184 

Pernicious  Malaria 203 

Hemoglobinuric  Fever 216 

Complications  and  Sequelae 232 


CHAPTER  VI 

Diagnosis 256 

Differential   Diagnosis •  284 

Diagnosis  of  Pernicious  Malaria 287 

Diagnosis  of  Hemoglobinuric  Fever     .    .        289 

13 


14  CONTENTS 

CHAPTER  VII  page 

Prognosis 292 


CHAPTER  VIII 

Prophylaxis 3°2 

Measures  Directed  for  the  Destruction  of  Mosquitoes 305 

Measures  Directed  Toward  the  Destruction  of  Parasites 315 

Measures  to  Prevent  the  Access  of  Mosquitoes 322 

Prophylaxis  of  Hemoglobinuric  Fever 332 


CHAPTER  IX 

Treatment 334 

References 3^8 

Index 397 


A    PRACTICAL   STUDY 

OF 

MALARIA 


DEADERICK 


A    PRACTICAL 

STUDY    OF    MALARIA 


CHAPTER  I 

INTRODUCTION 

A  certain  dusky  tropical  queen  was  wont  to  say  that  she 
did  not  fear  the  invasion  of  the  white  man,  for  she  had  two 
mighty  generals,  The  Fever  and  The  Forest. 

Malaria  has  been  one  of  civilization's  greatest  foes,  both  in 
time  of  war  and  in  peace.  Where  shot  and  shell  have  slain 
their  thousands,  malaria  has  slain  its  tens  of  thousands. 
Malaria  is  the  chieftain  of  the  army  of  disease.  Even  Napo- 
leon acknowledged  its  supremacy  when  he  wrote  his  minister 
of  war  on  the  occasion  of  the  disastrous  English  Walcheren 
expedition:  "We  are  rejoiced  to  see  that  the  English  them- 
selves are  in  the  morasses  of  Zealand.  Let  them  be  kept  only 
in  check,  and  the  bad  air  and  fevers  peculiar  to  the  climate  will 
soon  destroy  their  army."  It  is  said  that  the  French  crowed 
over  the  expedition  "with  the  force  of  reason,  the  bitterness 
of  sarcasm,  and  the  playfulness  of  ridicule."  How  accurately 
Napoleon's  prediction  was  verified  is  well  known. 

In  the  tropics  the  man  who  works  the  soil  digs  his  own 
grave.  Gigantic  commercial  enterprises  have  been  undertaken 
and  then  abandoned  on  account  of  the  havoc  wrought  by  this 
scourge.  Only  recently  has  it  been  recognized  that  the  medical 
man  must  precede  and  prepare  the  way  for  the  engineer  and 
the  laborer. 

But  warring  and  canal-digging  are  not  the  only  stages  upon 
which  the  malarial  tragedy  is  enacted.     Within  the  family,  at 


1 8  THE   STUDY  OF  MALARIA 

home,  the  disease  appears  in  a  varied  succession  of  forms, 
rapidly  fatal,  or  slowly  sapping  the  vitality,  influencing  the 
birth-rate,  longevity,  and  even  the  intelligence  and  morality 
of  entire  countries. 

In  highly  malarial  regions,  as  the  mortality  increases  the 
natality  diminishes  on  account  of  abortions  and  sterility.  Pre- 
mature senility  is  frequent  and  advanced  age  is  not  so  com- 
monly attained. 

Malaria,  leaving  its  subjects  anemic  and  neurotic,  is  respon- 
sible for  inertia,  loss  of  will  power,  intemperance,  and  general 
mental  and  moral  degradation.  Jones,  who  maintains  that 
malaria  was  a  potent  factor  in  the  decline  of  Greece  and  Rome, 
concludes  that  "malaria  made  the  Greek  weak  and  inefficient ; 
it  turned  the  sturdy  Roman  into  a  bloodthirsty  brute."  Mon- 
falcon  attributes  abortion,  infanticide,  universal  libertinism, 
drunkenness,  want  of  religion,  gross  superstition,  assassination, 
and  other  crimes  to  the  direct  influence  of  malaria. 

Malaria  costs  the  South  incalculable  wealth.  Besides  loss 
through  unfilled  acres,  diminished  earning  capacity,  loss  of 
time,  and  death,  it  produces  in  its  victims  a  disinclination  for 
work  whose  influence  cannot  be  estimated  in  money.  A  con- 
servative computation  of  the  loss  to  the  Southern  States 
through  malaria  is  fifty  millions  of  dollars  annually. 

The  importance  to  the  world  at  large  of  the  subject  of 
malaria  is  evidenced  by  the  fact  that  two  of  the  seven  Nobel 
prizes  in  medicine  which  have  been  awarded  have  been  granted 
for  discoveries  in  malaria — to  Ross  in  1902,  and  to  Laveran 
in  1907. 

The  history  of  malaria  may  be  traced  to  the  age  of  fable. 
The  story  of  Hercules  and  the  Hydra  is  a  familiar  one.  This 
monster  dwelt  in  the  morasses  in  the  neighborhood  of  the  Lake 
of  Lerna,  where  Hercules  was  dispatched  to  destroy  him.  As 
each  of  the  nine  heads  was  struck  off  two  new  ones  appeared. 
With  the  aid  of  his  faithful  servant,  Iolaus,  who  burned  each 
wound  caused  by  the  removed  head,  the  beast  was  finally  con- 
quered. Even  before  the  birth  of  Christ  this  myth  was  con- 
strued to  typify  the  reclamation  of  swamp  lands,  uninhabitable 
on  account  of  the  prevalence  of  malaria.     Antipater  wrote, 


INTRODUCTION  1 9 

"Hercules,  the  greatest  subduer  of  the  foggy  atmosphere  in 
times  past,  was  placed  among  the  gods  for  having  destroyed 
the  Hydra;  in  other  words,  for  having  reclaimed  the  marshy 
desert."  The  slaying  by  Apollo  of  the  Python  which  arose 
from  the  fertile  ground  after  the  recession  of  the  flood  is  simi- 
larly interpreted. 

More  than  one  thousand  years  before  the  birth  of  Christ 
malarial  disease  is  mentioned  in  the  Orphic  poems,  and  the 
tertian  and  quartan  types  are  alluded  to.  In  the  Iliad  of 
Homer  and  in  the  Wasps  of  Aristophanes  allusions  are  made 
to  a  fever  which  was  probably  malarial.  Paludism  was  proba- 
bly introduced  into  Greece  from  Egypt.  According  to  Groff 
the  word  AAT,  which  is  found  among  the  inscriptions  of  the 
temple  of  Denderah,  referred  to  a  disease,  doubtless  malaria, 
which  recurred  every  year  at  the  same  season. 

Hippocrates  divided  malarial  fevers  into  continuous  and 
intermittent,  which  he  subdivided  into  quotidian,  tertian,  and 
quartan.  He  recognized  the  etiologic  influence  of  season,  rains, 
and  stagnant  water,  and  the  dangers  of  malignancy,  dropsy, 
and  affections  of  the  spleen.  Plato  describes  splenic  enlarge- 
ment, and  other  early  Greek  writers  undoubtedly  refer  to 
malaria. 

References  by  Roman  writers  to  malaria  are  not  numerous, 
the  earliest  being  that  of  Plautus,  who  died  184  b.  c.  Cato 
speaks  of  "black  bile  and  swollen  spleen,"  and  Cicero,  Varro, 
Celsus,  Livy,  and  others  show  unmistakable  evidence  of  a 
knowledge  of  the  disease. 

Passing  over  the  development  during  the  middle  ages  of  the 
knowledge  of  malaria,  the  names  of  Morton,  Lancisi,  Syden- 
ham, and  Torti  appear. 

Morton,  1697,  gave  accurate  clinic  descriptions  of  the  perni- 
cious and  simple  intermittent  fevers,  and  attributed  them  to 
miasmatic  effluvia.  He  was  an  ardent  advocate  of  cinchona, 
whose  value  was  at  that  period  being  hotly  contested. 

Sydenham,  1723,  accurately  described  the  malarial  fevers. 
The  intermittent  fevers  he  divided  into  spring  and  autumn 
fevers.  He  justly  concluded  that  the  intermittent  and  con- 
tinuous forms  of  malaria  were  due  to  the  same  cause.     Syden- 


20  THE  STUDY   OF   MALARIA 

ham  ably  defended  cinchona,  and,  after  clinic  experiments  with 
its  use,  formulated  useful  rules  for  its  administration. 

Lancisi,  171 7,  stated  the  etiologic  relationship  between 
marshy  regions  and  malaria,  and  was  the  first  to  seek  for  a 
microscopic  organism  as  the  cause  of  the  disease. 

Torti,  1753,  wrote  an  exhaustive  treatise  upon  the  various 
forms  of  malaria.  His  classification  of  the  pernicious  forms 
has  become  classical.  Numerous  quotations  from  Torti's 
treatise  are  to  be  found  even  in  recent  works  upon  malaria. 

Varro,  118-29  b.  a,  expressed  the  opinion  that  malarial 
fever  was  caused  by  animals  so  minute  that  they  could  not  be 
seen  by  the  naked  eye,  and  which  enter  the  body  with  the  air 
through  the  nose  and  mouth.  Similar  opinions  were  held  by 
Columella,  Palladius,  and  Vitruvius.  Rasori  is  quoted  as  say- 
ing, "For  many  years  I  have  held  the  opinion  that  the  inter- 
mittent fevers  are  produced  by  parasites,  which  renew  the 
paroxysm  by  the  act  of  their  reproduction,  which  occurs  more 
or  less  rapidly  according  to  the  variety  of  their  species."  Le 
Diberder,  1869,  maintained  that  the  fever  was  due  to  the 
presence  in  the  blood  of  animals  which  preyed  upon  the  blood, 
and  that  the  paroxysms  depended  upon  reproductive  acts  be- 
tween which  apyrexia  occurred. 

Mitchel,  1849,  claimed  to  have  found  in  the  sputa  of  mala- 
rial subjects  fungous  spores  in  great  numbers,  which  he  be- 
lieved to  have  been  inspired  with  marsh  air  and  to  have  caused 
the  disease. 

Salisbury,  1866,  announced  the  discovery  in  the  urine  and 
sweat  of  malarial  patients  of  a  species  of  alga,  palmella,  com- 
mon on  the  marshy  regions  along  the  Ohio  and  Mississippi 
Rivers,  which  he  alleged  to  be  the  causative  element. 

Until  the  true  parasite  of  malaria  was  discovered  the  most 
widely  accepted  parasitic  theory  was  that  proposed  in  1879 
by  Klebs  and  Tommasi-Crudeli.  These  investigators  found 
constantly  present  in  the  mud  of  the  Roman  marshes  a  short 
bacillus.  They  were  able  to  cultivate  it  upon  fish  gelatine,  and 
when  injected  into  rabbits  produced  a  fever  similar  to  malaria. 
They  named  it  the  bacillus  malaria. 

The  malarial  parasites  were  undoubtedly  seen  and  described 


Fig.  i. — Charles  Louis  Alphonse  Laveran,  the  discoverer  of  the  parasite  of  malaria. 


INTRODUCTION  21 

before  Laveran  discovered  them.  In  1847  Meckel,  who  first 
discovered  malarial  pigment,  described  bodies  containing  pig- 
ment which  correspond  to  the  malarial  parasites.  Virchow, 
in  1849,  in  a  description  of  the  pigment,  depicted  cells  now 
known  to  be  parasites,  as  did  also  Frerichs  in  1866.  The  pig- 
ment was  observed  also  by  Dlauhy,  Heschl,  and  Planer.  None 
of  these  investigators,  however,  recognized  the  significance 
of  these  bodies,  and  their  parasitic  nature  was  not  suspected 
until  1880  by  Laveran,  to  whom  all  the  more  honor  is  due. 

Charles  Louis  Alphonse  Laveran  was  born  at  Paris,  June 
18,  1845.  He  entered  the  military  service  and  was  assigned 
to  Algeria,  where  his  brilliant  discovery  was  made  on  Novem- 
ber 6,  1880,  and  announced  to  the  Paris  Academy  of  Medicine 
November  23,  1880.  He  was  using  a  one-sixth  inch  dry  lens 
when  examining  the  blood.  He.  says,1  "My  first  researches 
date  from  1878 ;  at  this  time  I  was  on  duty  in  the  hospital  of 
Bone,  in  Algeria,  and  a  great  number  of  my  patients  were 
suffering  with  malarial  fever.  I  had  occasion  to  perform 
autopsies  upon  several  subjects  of  pernicious  malaria,  and  to 
study  melanemia  which  had  already  been  observed,  but  was 
not  considered  as  a  constant  change  in  malaria,  nor  as  a  spe- 
cific lesion  of  that  disease.  I  was  struck  by  the  singular  appear- 
ance of  granulations  of  black  pigment,  especially  in  the  liver 
and  in  the  cerebral  vessels,  and  I  endeavored  to  follow,  in 
the  blood  of  patients  suffering  with  malarial  fever,  the  study 
of  the  formation  of  pigment.  I  found  in  the  blood  leucocytes 
charged  with  pigment,  already  seen  by  other  observers,  but 
besides  melaniferous  leucocytes,  spherical  bodies,  varying  in 
size,  pigmented,  endowed  with  amoeboid  motion,  and  pig- 
mented crescentic  bodies  attracted  my  attention.  I  supposed 
at  that  time  that  these  were  parasites. 

"In  1880,  at  the  military  hospital  of  Constantine,  I  discov- 
ered, besides  the  spherical  pigmented  bodies,  in  the  blood  of 
a  malarial  subject  filiform  elements  resembling  flagella,  which 
writhed  with  great  vivacity  and  displaced  the  neighboring  cor- 
puscles. From  then  I  had  no  further  doubt  as  to  the  parasitic 
nature  of  these  elements  which  I  had  found  in  the  blood." 

Laveran's  discovery  was  not  accepted  by  the  medical  world 


22  THE   STUDY   OF  MALARIA 

until  several  years  later;  now  it  has  been  confirmed  the  world 
over.  Among  Americans  who  first  corroborated  Laveran's 
views  may  be  mentioned  Sternberg,  Councilman  and  Abbott, 
Osier,  James,  Dock,  Thayer  and  Hewetson,  Barker,  Woldert 
and  Welch. 

The  discoveries  of  Golgi  in  1885  were  of  great  importance 
with  reference  to  the  life  history  of  the  parasite.  He  was  able 
to  follow  tertian  and  quartan  parasites  throughout  the  endogen- 
ous cycle  of  development,  and  showed  that  a  close  relationship 
existed  between  certain  phases  of  parasitic  growth  and  certain 
stages  of  the  paroxysm.  Other  Italian  investigators  proved 
the  same  for  the  estivo-autumnal  parasites. 

A  vague  suspicion  that  malaria  and  mosquitoes  were  in  some 
indefinite  way  connected  has  been  entertained  in  certain  coun- 
tries for  a  long  period.  A  definite  mosquito  theory,  however, 
was  born  in  America.  While  reference  is  sometimes  made  to 
a  paper  on  the  "Mosquital  Origin  of  Malarial  Disease,"  sup- 
posed to  have  been  published  by  Dr.  John  Crawford  in  the 
Baltimore  Observer,  1807,  no  sucn  article  has  been  found, 
and  the  reference  is  probably  erroneous. 

In  1848  Dr.  Josiah  Nott,2  of  Mobile,  published  a  paper  upon 
yellow  fever,  in  which  he  maintained  the  dissemination  of  that 
disease  by  insects,  and  suggested  that  malaria  was  spread  by 
the  "mosquito  of  the  lowlands." 

The  most  complete  theory  was  proposed  by  King3  in  1883. 
His  views  are  supported  by  nineteen  arguments,  most  of  which 
are  incontestable  at  the  present  day. 

That  mosquitoes  are  agents  in  the  spread  of  malaria  was 
advanced  by  Koch  in  1884,  by  Laveran  in  1884,  by  Fliigge  in 
1 89 1,  by  Manson  in  1894,  and  by  Bignami  in  1896. 

Undertaking  the  work  at  Manson's  suggestion,  and  after 
several  years  (1895-1898)  of  toil  and  discouragement,  Ross 
proved  conclusively  that  certain  species  of  mosquitoes  are  con- 
cerned in  the  dissemination  of  malaria.  The  debt  owed  him 
by  mankind  was  acknowledged  by  the  gift  of  a  Nobel  prize; 
his  own  feelings  over  the  discovery  are  expressed  in  these  lines, 
which  he  wrote : 


Fig.   2. — Major  Ronald  Ross,  the  discoverer  of  the  role  of  the  mosquito. 


INTRODUCTION  23 

"This   day  relenting   God 

Hath  placed  within  my  hand 
A  wondrous  thing,  and  God 
Be  praised.    At  his  command 

"Seeking  His  secret  deeds, 

With  tears  and  toiling  breath, 
I   find  thy  cunning   seeds, 
Oh  million-murdering  death. 

"I  know  this  little  thing 
A  myriad  men  will  save ; 
Oh,  death,  where  is  thy  sting, 
Thy  victory,  oh  grave?" 

A  discovery,  secondary  in  importance  only  to  those  of 
Laveran  and  of  Ross,  was  made  by  MacCallum  in  1898,  who 
demonstrated  that  the  flagella  represent  male  sexual  elements, 
analogous  to  spermatozoa. 

HISTORY  OF  HEMOGLOBINURIC  FEVER 

It  is  probably  unique  in  historical  pathology  that  a  complex 
of  symptoms  so  striking  as  hemoglobinuric  fever  should  have 
such  an  obscure  history.  As  this  obscurity  is  intimately  asso- 
ciated with  the  etiology  and  symptomatology  of  the  condition 
an  investigation  of  some  of  the  factors  in  its  history  is  not 
without  interest.  After  a  short  statement  of  the  history  of 
hemoglobinuric  fever  we  will  briefly  consider  how  far  it  has 
been  influenced  by  (1)  its  confusion  with  bilious  remittent 
fever  and  yellow  fever,  (2)  the  introduction  of  cinchona  bark 
and  its  alkaloids  into  the  treatment  of  malaria,  and  (3)  the 
advent  of  Europeans  into  endemic  regions. 

In  the  years  from  1850  to  1853  blackwater  fever  was  de- 
scribed by  Lebeau,  Daulle,  and  Leroy  de  Mericourt,  physicians 
of  the  French  navy,  who  observed  it  in  Madagascar,  and  espe- 
cially on  the  Island  of  Nossi  Be,  off  the  northwest  coast  of 
the  former  island.  They  named  the  condition  icteric  pernicious 
fever.  In  1861  cases  observed  in  the  Antilles,  Guiana,  and 
Senegal  were  described  by  Dutrouleau  as  hematuric  bilious 
fever.  In  the  early  sixties  Barthelemy-Benoit  also  described 
hematuric  bilious  fever,  and  in  1874  appeared  the  monograph 
of  Berenger-Feraud  on  melanuric  bilious  fever.     This  writer 


24  THE   STUDY   OF  MALARIA 

states  that  the  disease  has  existed  in  Goree  since  1845,  and  in 
St.  Louis,  in  Senegal,  according  to  the  hospital  records  of  that 
city,  at  least  since  1820,  shortly  after  the  settling  of  the  Euro- 
peans there.  The  first  twenty-three  settlers  at  Gabun,  in  1843, 
were  attacked  with  blackwater  fever  and  almost  all  of  them 
died.    A  great  increase  in  frequency  has  occurred  since  1850. 

Crosse4  believes  his  own  case,  in  1888,  to  be  the  first  on 
record  in  the  Niger  Territories,  though  he  states  that  the 
disease  was  said  by  old  coasters  to  have  existed  in  the  Niger 
Delta  since  1882.  F.  Plehn5  does  not  believe  the  disease  to 
be  of  recent  introduction  into  West  Africa,  but  attributes  its 
comparatively  late  recognition  to  two  facts — first,  that  the 
susceptible  population,  who  formerly  lived  as  traders  on  an- 
chored hulks,  began  to  take  up  their  abode  on  the  shore; 
second,  that  the  disease  was  formerly  confounded  with  yellow 
fever.  It  has  been  known  in  Senegambia  since  1855,6  and  in 
the  Dutch  East  Indies  since  the  Atjeh  War,  1874-78.7  Cal- 
mette  saw  a  number  of  cases  in  Gabun  in  1886-87,  an<^  Fluit, 
in  San  Juan  del  Stir,  has  seen  numerous  cases  since  1850.8 
The  condition  was  not  described  in  India  until  1855,  and 
Sambon9  regards  this  as  conclusive  of  its  recent  introduction, 
as  "it  would  be  absurd  to  think  that  it  could  have  escaped  the 
attention  of  such  men  as  Annesley,  Chevers,  Carter,  Martin, 
Fayrer,  Morehead,  and  Maclean  had  they  met  with  it." 

Dr.  Elliotson,10  in  1832,  mentioned  a  case  of  ague  accom- 
panied by  a  discharge  of  bloody  urine  during  the  cold  stage. 

Todd,10  in  1849,  asserted  that  "a  state  of  general  cachexia, 
such  as  often  occurs  in  scurvy,  may  bring  on  hematuria,  or 
such  as  results  from  an  aguish  state  brought  on  by  the  malaria 
of  marshy  districts." 

In  the  United  States  hemoglobinuric  fever  was  first  de- 
scribed by  Dr.  J.  C.  Cummings,ia  of  Monroe,  Louisiana,  in 
1859.  He  reported  6  cases,  and  refers  to  numerous  cases 
during  the  previous  season.  Faget12  treated  the  disease  as 
early  as  1859,  and  states  that  cases  with  hematuria  and 
hematemesis  had  frequently  been  seen  in  New  Orleans  and 
been  mistaken  for  yellow  fever.  Inasmuch  as  Faget  consid- 
ered hematemesis  a  common  symptom  of  hemoglobinuric  fever, 


INTRODUCTION 


25 


it  is  possible  that  he  himself  confounded  the  two  diseases  in 
some  instances.  In  1867  Dr-  T.  C.  Osborn,13  of  Greensboro, 
Ala.,  observed  10  cases,  5  of  which  ended  fatally,  some  with 
anuria  and  uremia.  All  the  patients  had  been  repeatedly  at- 
tacked with  malaria.  A  few  months  later  his  son,  Dr.  J.  D. 
Osborn,14  read  a  paper  before  the  Greensboro  Medical  Society, 
from  which  it  is  evident  that  the  disease  was  becoming  more 
prevalent,  and  that  the  country  people  were  regarding  it  as 
yellow  fever.  Dr.  H.  C.  Ghent,15  of  Port  Sullivan,  Texas,  in 
1866  reported  hemoglobinuric  fever  endemic  in  parts  of  Texas. 
In  March,  1869,  Dr.  R.  F.  Michel,  of  Montgomery,  Ala.,  read 
a  paper  before  the  Medical  Association  of  the  State  of  Alabama 
in  which  he  spoke  of  the  disease  as  "a  malignant  malarial 
fever,  following  repeated  attacks  of  intermittent,  characterized 
by  intense  nausea  and  vomiting,  very  rapid  and  complete  jaun- 
diced condition  of  the  surface  as  well  as  most  of  the  internal 
organs  of  the  body,  an  impacted  gall-bladder,  and  hemorrhages 
from  the  kidneys.  These  phenomena  presented  themselves  in 
an  almost  uninterrupted  link,  attended  by  remissions  and  exac- 
erbations. It  is  a  fever  peculiar  to  the  United  States."  He 
recorded  the  morbid  anatomy  in  one  of  his  fatal  cases.  In 
Arkansas  hemoglobinuric  fever  was  first  recorded  by  Dr.  E. 
R.  Duvall,  of  Fort  Smith,  in  a  paper  read  before  the  State 
Society  in  1871.  He  believed  the  case  he  recorded  to  be  the 
first  to  occur  in  the  State.  This  paper  is  said  to  be  a  model 
of  accurate  clinic  observation.  In  1880  Dr.  G.  B.  Malone,  in 
Monroe  County,  Arkansas,  reported  155  cases  met  in  his  prac- 
tice. The  affection  was  first  reported  in  Georgia  by  Dr.  W. 
A.  Greene,  of  Americus,  in  1872,  and  in  North  Carolina  by 
Dr.  Norcom,  of  Edenton,  in  1874.  Norcom  asserts  that  the 
disease  did  not,  as  some  claimed,  make  its  first  appearance  a 
few  years  ago,  but  that  it  had  long  been  recognized.  Dr. 
McDaniel,10  of  Camden,  Alabama,  described  hemoglobinuric 
fever  in  1874,  and  says,  "In  calling  up  my  own  reminiscences, 
I  am  sure  that  I  have  occasionally  ever  since  my  boyhood  seen 
isolated  cases  of  what  was  considered  intense  bilious  fever  with 
the  surfaces  and  under  tissues  stained  deeply  yellow  and  with 
the  urine  deep  red.     They  were  nearly  all   fatal,  and  were 


26  THE   STUDY   OF  MALARIA 

called  in  older  phrase  "bilious  congestive,"  and  in  more  recent 
"pernicious  bilious.''  I  have  also,  but  more  rarely,  known 
groups  of  similar  cases  associated,  say  3  or  4  cases  occurring 
on  the  same  premises  or  in  the  same  family,  about  the  same 
time.  All  such  cases,  in  addition  to  the  deep  so-called  bilious 
color  and  the  red  urine,  had  jactitation,  suspirous  breathing, 
inordinate  thirst,  and  vomiting  of  various  shaded  and  tinted 
so-called  bilious  matters.  By  diligently  inquiring  I  have  ascer- 
tained that  very  many  old  physicians,  some  of  whom  have 
now  retired  from  practice,  are  satisfied  that  they  have  observed 
similar  cases,  sometimes  singly  and  sometimes  in  groups. 

The  late-lamented  Dr.  A.  G.  Mabry,  in  a  report  of  a  case 
of  intermitting  icterode  hematuric  fever  made  to  this  associa- 
tion in  1870,  says,  "It  is  a  mistake  to  suppose  that  this  is  a 
new  form  of  disease.  More  than  twenty-five  years  ago  I 
treated,  in  the  vicinity  of  Selma,  cases  of  intermitting  fever 
presenting  in  a  marked  degree  all  the  symptoms  characteristic 
of  these  cases  at  the  present  day." 

The  acrimonious  dispute  of  the  earliest  writers  on  the  sub- 
ject of  what  constituted  the  coloring  matter  of  the  urine  is 
parallelled  only  by  that  occurring  later  concerning  quinine  in 
the  treatment.  While  Daulle  and  Berenger-Feraud  stoutly 
maintained  that  the  dark  color  was  due  to  the  presence  of  bile 
in  the  urine,  Dutrouleau,  Pellarin,  Barthelemy-Benoit,  Anto- 
niades,  and  Corre  ascribed  it  to  blood.  It  is  remarkable  that 
none  of  the  first  American  waiters  attributed  the  color  of 
the  urine  to  bile,  but  considered  it  due  to  blood.  Corre  ( 1881 ) 
and  Karamitsas  (1882)  proved  that  the  process  was  a  hemo- 
globinuria instead  of  a  hematuria. 

The  credit  of  first  directing  attention  to  the  etiologic  rela- 
tion between  quinine  and  hemoglobinuric  fever  is  generally 
credited  to  Tomaselli,  who  published  his  first  observations  in 
1874,  but  this  is  an  error.  At  a  meeting  of  the  Greek  Medical 
Society,  November  6,  1858,  Veretas15  reported  that  the  major- 
ity of  physicians  practising  in  the  marshy  regions  of  Greece 
had  noticed  hematuria  following  the  administration  of  quinine. 
He  adds,  "Among  these  observers  my  father  has  a  place,  hav- 
ing attentively  observed  this  action  of  the  medicament  not 


INTRODUCTION  27 

only  in  several  other  persons,  but  in  himself  also,  unfortunately, 
as  he  was  for  a  long  time  tormented  with  intermittent  fever 
during  his  long  residence  at  Vonitsa."  Konsola15  is  said  to 
have  observed  similar  cases  in  1858.  During  this  year,  also, 
Antoniades  published  an  article  on  "Hemorrhages  and  Par- 
ticularly Hematuria  in  Intermittent  Fever,"  in  which  he  op- 
poses the  theory  that  quinine  is  a  cause.  Other  Greek  physi- 
cians whose  observations  were  published  before  those  of  Toma- 
selli  are  Papavassilou,  Rizopoulos,  and  Karamitsas. 

1.  The  close  relationship  between  malaria  and  blackwater 
fever  renders  it  easily  understood  why  the  latter  might  have 
been  confounded  with  bilious  remittent  fever.  Moreover,  the 
early  pyretologists  almost  completely  ignored  the  condition  of 
the  urine  in  fevers.  Hence,  in  a  clinical  scene,  preceded  by  or 
opened  with  ordinary  malarial  paroxysms  and  characterized 
by  dark  urine,  between  the  color  of  which  and  the  bilious  urine 
of  bilious  remittent  fever  there  are  all  degrees,  it  is  slight 
wonder  that  the  two  conditions  were  confounded. 

This  probably  occurred  chiefly  in  India  and  to  a  less  extent 
in  certain  portions  of  Africa  and  America.  One  is  struck,  on 
reading  accounts  of  the  Indian  fevers,  with  the  description  of 
the  intense  jaundice  of  the  skin  and  scleras,  out  of  all  propor- 
tion to  this  symptom  in  the  bilious  remittent  fevers  of  the 
present  day.  In  fact,  some  of  these  descriptions — for  instance, 
Johnson's16  of  his  first  case  in  India — lack  only  the  mention 
of  the  characteristic  urine,  about  which  the  author  is  altogether 
silent,  to  make  a  fairly  complete  case  of  hemoglobinuric  fever. 
Cleghorn17  graphically  depicts  what  he  regards  as  a  form  of 
tertian  fever,  accompanied  with  hemorrhages,  dark  urine,  deep 
jaundice,  and  other  symptoms  of  hemoglobinuric  fever.  Since 
it  is  reasonably  certain  that  there  was  no  yellow  fever  in 
Minorca  during  the  period  of  Cleghorn's  sojourn  in  the  island, 
namely  from  1744  to  1749,  it  may  reasonably  be  inferred  that 
he  saw  cases  of  blackwater  fever. 

The  fact  that  the  early  history  of  hemoglobinuric  fever  opens 
with  disputes  as  to  whether  the  coloring  matter  of  the  urine 
was  due  to  blood  or  to  bile  is  evidence  of  the  confusion  by 
some  observers  between  hemoglobinuric  fever  and  bilious  re- 


28  THE   STUDY   OF   MALARIA 

mittent  fever,  since  formerly  bile  and  malaria  were  practically 
synonymous. 

It  has  been  mentioned  that  the  first  reliable  records  of  the 
existence  of  hemoglobinuric  fever  were,  according  to  Berenger- 
Feraud,  those  of  the  hospital  of  St.  Louis  in  Senegal,  where 
it  is  shown  to  have  existed  as  early  as  1820.  It  is  a  singular 
coincidence  that  this  city  afforded,  in  1778,  the  first  epidemic 
of  yellow  fever  occurring  in  Africa.18  Later  Plehn5  gave  as 
one  of  his  reasons  for  believing  that  hemoglobinuric  fever  was 
not  a  new  disease  in  West  Africa,  that  it  had  formerly  been 
mistaken  for  yellow  fever.  Besides  Senegal,  two  of  the  other 
regions  where  hemoglobinuric  fever  was  first  seen,  the  West 
Indies  and  Guiana,  were  yellow-fever  foci.  In  the  United 
States  we  have  the  early  statement  of  Dr.  J.  D.  Osborne  that 
the  condition  was  then  regarded  as  yellow  fever. 

The  similarity  of  the  symptoms  and  the  relative  immunity 
of  the  black  race  to  both  diseases  render  the  mistake  somewhat 
excusable.  As  recently  as  1897  Below448  maintained  the  iden- 
tity of  yellow  fever  and  blackwater  fever. 

2.  Cinchona  bark  was  introduced  into  Europe  in  1640  by 
the  Countess  del  Cinchon,  wife  of  the  vice-regent  of  Peru,  in 
whose  honor  it  has  received  its  name.  The  efficacy  of  the  bark 
in  malaria  was  first  known  to  the  Indians  in  the  region  of 
Loxa,  in  the  southern  portion  of  Ecuador.  The  Corregidor 
of  Loxa,  hearing  of  the  severe  illness  of  the  countess  with 
tertian  fever  at  Lima,  in  1638,  advised  her  physician,  de  Vega, 
to  give  the  bark  a  trial,  which  effected  a  prompt  cure,  and  in 
those  days  was  regarded  as  nothing  short  of  miraculous. 
When  the  countess  returned  to  Spain  she  took  a  supply  of  the 
bark  with  her.  Here  it  seems  first  to  have  been  employed 
chiefly  by  the  Jesuits,  who  introduced  it  into  Rome  in  1649. 
It  was  then  known  as  countess'  powder,  or  Jesuits'  powder. 
Its  use  was  antagonized  by  other  religious  denominations  and 
by  the  medical  profession.  Bark  was  imported  into  England 
in  1671  by  Sir  Robert  Talbot,  an  English  quack,  who  kept  the 
remedy  a  secret  and  sold  it  for  one  hundred  louis  d'or  per 
pound.  Louis  XIV,  who  was  attacked  with  a  rebellious  and 
severe  intermittent  in  the  year  1679,  was  cured  by  Talbot  with 


INTRODUCTION  29 

a  concentrated  vinous  tincture  of  the  bark,  purchased  and 
made  public  the  secret  remedy,  for  which  he  paid  £48,000  and 
a  life  annuity  of  £2000. 

In  India  the  remedy  was  employed  by  Bogue20  as  early  as 
1657.  In  these  times  in  Spanish- America,  where  the  bark  was 
indigenous,  extraordinary  methods  were  employed  to  prevent 
the  nature  of  the  drug  becoming  recognized.  But  during  the 
eighteenth  century  cinchona  bark  was  almost  universally 
known.  Lind  is  said  to  have  employed  in  Lower  Senegal, 
during  1765,  over  140  pounds  of  the  bark.  In  1714  Ramaz- 
zini21  wrote  that  should  a  fever  patient  die  it  was  considered  a 
crime  not  to  have  employed  cinchona.  In  fact,  so  widespread 
was  the  use  of  large  doses  of  bark  that  Calmenero  (1647), 
Casati  (1661),  Daval  (1684),  Ramazzini  (1714),  and  others 
wrote  vehemently  against  the  abuse  of  the  drug. 

Pelletier  and  Caventou,  in  1820,  succeeded  in  isolating 
quinine  from  the  bark. 

The  institution  of  cinchona  plantations  in  Java  in  1854  and 
in  Ceylon  in  1859  caused  a  drop  in  the  price  of  quinine,  which 
had  formerly  sold  for  its  actual  weight  in  gold,  to  one-twenti- 
eth the  original  price. 

Marchiafava  and  Bignami22  seek  to  explain  the  seeming  late 
appearance  of  hemoglobinuric  fever  by  the  use  of  quinine 
becoming  prevalent  at  the  time  when  the  disease  was  first 
described.  It  is  probable  that  this  factor  has  caused  an  increase 
in  certain  localities,  but  a  comparison  of  the  history  of  the 
disease  with  that  of  the  drug  shows  no  very  intimate  chrono- 
logic relations.  Further,  blackwater  fever  is  on  the  decrease 
in  some  regions  where  the  use  of  quinine  is  becoming  more 
general.  This  is  reported  to  be  the  case  in  German  East  Africa 
by  Meixner,23  in  Cameroon  by  Ziemann,23  in  Togo  by  A. 
Plehn,24  and  by  Kohlbrugge7  in  the  Malay  Archipelago.  The 
large  number  of  cases  occurring  without  the  previous  use  of 
quinine  should  also  be  considered. 

3.  A  consideration  of  the  importance,  in  the  history  of 
hemoglobinuric  fever,  of  the  immigration  of  Europeans  into 
regions  where  the  condition  is  endemic  involves  the  history 
of  the  tropics  and  subtropics.     This  factor  is  manifestly  an 


30  THE   STUDY  OF  MALARIA 

essential  in  countries  where  the  natives  are  nearly  immune,  as 
in  parts  of  Africa.  Historic  events,  which  were  probably 
potent  in  the  development  of  blackwater  fever,  were  the  dis- 
covery of  America,  the  Portuguese  discoveries  and  settlements 
on  the  coast  of  Africa,  the  African  slave  trade  and  the  later 
efforts  to  abolish  the  same,  the  advent  to  Africa  of  mission- 
aries and  explorers,  especially  in  the  early  part  of  the  nine- 
teenth century,  and  the  operations  of  the  East  India  Company. 
The  accession  of  Europeans  was  influential  in  the  history 
of  hemoglobinuric  fever  in  several  ways — by  the  increase  of 
susceptible  population,  by  the  importation  of  quinine,  and  by 
the  advent  of  physicians  competent  to  recognize  and  to  describe 
the  disease. 


CHAPTER  II 

GEOGRAPHIC  DISTRIBUTION 

North  America. — In  the  United  States  it  is  chiefly  the 
southeastern  portion  in  which  malaria  is  most  prevalent.  Along 
the  Atlantic  coast,  south  of  New  York  and  especially  the  low- 
lands of  Maryland  and  of  Virginia,  and  in  the  Carolinas, 
Georgia,  and  Florida  the  disease  occurs  frequently.  Along  the 
Gulf  coast  and  up  the  Mississippi  River  and  its  tributaries 
malaria  is  widely  prevalent.  The  portions  of  the  States  lying 
along  the  Appalachian  Range  are  almost  exempt,  but  the  dis- 
ease appears  as  the  Mississippi  River  and  the  Atlantic  coast 
upon  either  side  are  approached.  West  of  the  Mississippi, 
Arkansas,  Louisiana,  and  Texas  present  the  most '  numerous 
foci  of  malaria.  In  portions  of  Pennsylvania  and  New  York 
autochthonous  cases  are  not  infrequently  observed.  In  the 
more  southern  New  England  States  malaria  is  still  encountered, 
and  in  some  places  is  even  increasing  in  frequency.  In  the 
neighborhood  of  the  Great  Lakes  malaria  is  very  rare,  except- 
ing, possibly,  that  of  Lake  Erie  and  of  Lake  Michigan.  In 
the  Central  States  malaria  has  almost  or  quite  disappeared, 
except  in  certain  low  river  valleys.  Along  the  Pacific  coast 
the  disease  is  not  so  frequent  as  along  the  Atlantic.  In  Wash- 
ington it  occurs  in  the  Puget  Sound  Basin  and  the  Columbia 
River,  Chehalis,  and  the  Yakima  valleys.  In  Oregon  malaria 
is  found  in  the  Columbia,  Williamette,  Rogue,  and  the  Uma- 
tilla valleys,  and  in  California  in  the  Sacramento,  San  Joaquin, 
Tulare,  Kern,  and  Santa  Clara  valleys.  In  certain  parts  of 
New  Mexico  malaria  is  occasionally  met  with. 

Canada  is  free  from  paludism  except  along  the  northern 
shore  of  Lake  Ontario. 

In  Mexico  severe  forms  of  malaria  occur,  particularly  in 
the  low  coast  regions. 

31 


32  THE    STUDY    OF    MALARIA 

Malaria  abounds  in  Central  America  along  the  Atlantic  coast 
and  to  a  less  extent  upon  the  Pacific  side. 

South  America. — The  eastern  coast  of  South  America  is 
more  intensely  infested  with  malaria  than  is  the  western  coast. 
Venezuela  (in  the  valleys),  Guiana,  and  the  greater  portion  of 
Brazil  are  highly  malarial.  Portions  of  Paraguay  and  of 
Bolivia  afford  a  great  many  cases,  while  the  disease  is  much 
less  prevalent  in  Uruguay  and  almost  absent  from  the  Argen- 
tine Republic.  On  the  Pacific  border  the  deep  valleys  of  Peru 
and  of  Ecuador  are  malarial  centers. 

The  entire  island  of  Cuba  is  malarial  to  a  greater  or  less 
extent,  as  is  also  Jamaica.  Of  the  Lesser  Antilles,  St.  Vin- 
cent, Antigua,  and  Barbadoes  are  relatively  exempt.  Malaria 
is  said  to  be  almost  unknown  in  the  Bermudas. 

Europe. — Great  Britain,  once  infested,  is  now  free  from 
endemic  malaria.  In  Germany  the  disease  occurs  infrequently 
in  the  Rhine  and  Danube  valleys  and  near  the  mouths  of  rivers 
along  the  coast.  Malaria  is  met  in  Holland,  chiefly  upon  the 
island  of  Zeeland  and  in  North  and  South  Holland.  The 
valley  of  the  Danube,  in  Austria,  affords  a  considerable  num- 
ber of  cases.  There  are  few  regions  in  Hungary  in  which  the 
disease  does  not  occur,  but  it  is  especially  along  the  western 
half  of  the  southern  border  that  it  is  prevalent.  The  marshes 
along  the  west  coast  and  in  the  south  of  France  give  rise  to 
a  number  of  cases  of  malaria.  In  Spain  and  Portugal  malaria 
occurs  in  the  coast  regions  and  in  the  larger  river  valleys.  The 
disease  is  practically  unknown  in  Norway,  but  is  occasionally 
reported  from  Sweden,  as  well  as  from  certain  of  the  islands 
of  Denmark.  In  Russia  it  is  in  the  southern  portion,  particu- 
larly along  the  coasts  and  along  the  valleys  of  the  rivers  flow- 
ing southward,  that  malaria  is  encountered.  Cases  are  occa- 
sionally observed  in  the  southwest  of  Switzerland.  The  por- 
tions of  Bulgaria  most  highly  malarial  are  the  Danube  valley, 
the  coast  region,  and  the  southern  part.  Almost  the  whole  of 
Italy  is  sorely  afflicted  with  malaria,  as  are  also  Sicily  and 
Sardinia.  Greece  is  the  most  severely  scourged  country  of 
Europe.     It  is  said  that  in  the  plains  of  Thessaly,  Phthiotis, 


GEOGRAPHIC    DISTRIBUTION  33 

Acarnania,  Boeotia,  Elis,  Messenia,  Argos,  and  Laconia  hardly 
a  single  inhabitant  escapes  the  disease. 

Asia. — Asia  Minor,  Arabia,  and  Persia  present  foci  of  mala- 
ria, both  in  the  coast  neighborhoods  and  in  the  interior  low- 
lands. In  the  swampy  regions  of  Afghanistan  and  Beloochis- 
tan  malaria  is  common  and  severe.  In  India  portions  of  the 
northwest  provinces  and  of  the  Bengal  and  Bombay  Presiden- 
cies are  intensely  malarial.  The  foothills  of  the  Himalayas, 
the  Duars,  and  Terai  are  famous  malarial  seats.  Both  the 
coast  regions  and  the  interior  highlands  of  Ceylon  are  endemic 
territory.  Burmah,  Siam,  the  Malay  Peninsula,  and  French 
Indo-China  are  malarial  in  portions  of  their  extent,  and  parts 
of  China  are  intensely  infested.  Malaria  is  found  in  Japan, 
Formosa,  and  the  Philippines,  and  portions  of  the  East  Indies 
are  among  the  most  highly  malarial  regions  of  the  world. 

Africa. — On  the  west  coast  the  territory,  between  the 
Senegal  and  the  Congo  Rivers,  is  headquarters  for  malaria  of 
malignant  type.  Approaching  South  Africa  the  disease  dimin- 
ishes in  frequency  and  in  severity.  On  the  east  the  region 
from  Delagoa  Bay  to  Eritrea  is  malarial.  In  the  interior  of 
Central  Africa,  excepting  the  high  elevations,  malaria  is  wide- 
spread. Malaria  abounds  in  Madagascar  excepting  upon  the 
northeast  coast  and  the  mountainous  interior.  Reunion  and 
Mauritius  are  also  malarial.  In  Egypt  it  is  chiefly  the  region 
overflowed  by  the  Nile  in  which  the  disease  is  most  prevalent. 
Malaria  abounds  about  the  coasts  and  marshes  of  Algeria. 

In  Australia  malaria  occurs  from  Cape  York  to  Brisbane, 
on  the  east  coast,  diminishing  toward  the  south.  New  Zealand 
is  apparently  free  from  malaria,  and  the  Sandwich  Islands  and 
most  of  the  other  Pacific  islands  are  remarkably  exempt. 

The  relative  frequency  of  the  forms  of  malarial  infection 
varies  greatly.  It  may  be  stated  as  a  general  proposition  that 
the  quartan  is  the  rarest  form,  the  tertian  is  the  form  prevail- 
ing in  temperate  regions,  and  the  estivo-autumnal  in  warm  and 
hot  climates.  There  are  regions,  however,  in  which  the  quartan 
predominates,  as  in  certain  portions  of  Italy  and  of  India ; 
in  other  localities  it  is  the  only  form  of  malaria  present,  as 
upon  the  island  Merite,  of  the  Bismarck  Archipelago. 
3 


34  THE   STUDY   OF  MALARIA 

The  following  table  shows  the  relative  frequency  of  the 
types  of  malaria  in  various  regions : 


Locality.  Authority. 

Texas    Moore25   

Georgia     Curry26    

Camp  Wikoff Ewing27    

New    Orleans Charity  Hospital  Records2' 

Baltimore  Thayer  and  Hewetson29. . . 

Panama    Kendall30    

St.   Lucia Gray  and   Low31 

Panama    Gorgas32    

Italy    Koch33   

Italy    Koch34   

Greece    Cardamatis  and  Diamessis31 

Bulgaria   Mollow30   

Italy Italian   Statistics37 32,392   6,846 

British   Malaya Wright38    

British   Malaya Watson38 

Philippines Craig39  

India   Hope40  

Cyprus    Williamson41    

East  Indies Koch"   

Philippines   Chamberlain43    

India    Rogers44    1,372 

India    Buchanan45 

Assam  Bentley40  

Japan Tsuzuki47    

Togo  Ziemann48  

German  East  Africa . . .  Meixner49   

German  East  Africa. . .  Grothusen49    

Senegal  Thiroux  and  d'Anf reville 

German  East  Africa. . .  Kudicke61    

German  East  Africa. . .  Exner52   

German  East  Africa . . .  Ollwig02  

German  East  Africa. . .  Schornich52    

Infections  with  more  than  one  form  of  the  parasite  are  not 
uncommon.  Of  these  a  combination  of  the  tertian  and  the 
estivo-autumnal  is  the  most  frequent,  the  tertian  with  the  quar- 
tan being  rare,  and  the  three  forms  together  very  rare. 

GEOGRAPHIC  DISTRIBUTION  OF  HEMOGLOBINURIC  FEVER 

In  North  America  hemoglobinuric  fever  is  found  in  the 
Southern  States,  especially  parts  of  Texas,  Louisiana,  Arkan- 
sas, Mississippi,  Tennessee,  Alabama,  Georgia,  Florida,  North 
Carolina,  South  Carolina,  and  Virginia.  It  is  prevalent  in 
Central  America,  particularly  in  Honduras,  Nicaragua,  and 
Costa  Rica.  It  is  found  in  the  Greater  Antilles,  but  appears 
to  be  rare  in  Hayti.    In  the  Lesser  Antilles  it  is  more  common 


Tertian.  Quar- 

Estivo-au- 

tan. 

tumnal. 

23 

0 

30 

34 

0 

16 

74 

0 

261 

373 

I 

203 

33* 

5 

l88 

22 

0 

29I 

12 

2 

109 

4,812 

8 

IO,8l5 

32 

5 

78 

202 

15 

191 

87 

3 

145 

99 

10 

67 

12,392 

6,846 

23,520 

78 

56 

117 

T9 

4 

28 

98 

8 

272 

217 

933 

547 

12 

8 

4 

57 

119 

123 

55 

3 

62 

1,372 

71 

1,311 

56 

12 

118 

134 

46 

74 

345 

12 

107 

1 

7 

32 

5 

1 

102 

5 

7 

68 

7 

44 

266 

3 

2 

118 

11 

4 

328 

7 

0 

134 

1 

2 

130 

GEOGRAPHIC    DISTRIBUTION 


35 


on  the  islands  of  Guadeloupe  and  Martinique.  Numerous  cases 
have  been  reported  from  Panama. 

In  South  America  hemoglobinuric  fever  prevails  more  nota- 
bly on  the  north  and  east  coasts,  in  Venezuela,  Guiana,  and 
Brazil,  at  least  as  far  south  as  Rio  de  Janeiro. 

It  is  rare  in  Italy,  but  rather  more  common  in  Sicily,  Sar- 
dinia, and  Greece.  Otto53  has  reported  an  autochthonous  case 
from  Krakau.  It  has  appeared  in  some  of  the  valleys  of  Spain, 
and,  according  to  Schoo,  was  formerly  observed  in  Holland. 

The  regions  in  India  in  which  hemoglobinuric  fever  is  en- 
demic are  as  follows :  Between  the  Ganges  River  and  the 
Himalayas  in  Behar  Province;  between  the  Godavari  and  the 
Mahandi  Rivers  in  the  Madras  Presidency;  a  region  in  the 
Punjab  between  Meerut  and  the  Indus  River ;  a  region  of  which 
Nagpur  is  the  center;  certain  localities  in  the  region  of  Bom- 
bay ;  and  in  Assam  and  in  upper  Burmah.  It  is  found  in  Asia 
Minor,  Cyprus,  and  Syria  (being  common  in  Palestine),  the 
Malay  Peninsula,  Siam,  Cochin-China,  Tonking,  and  other 
portions  of  French  Indo-China,  and  in  Southern  China.  In 
the  East  Indies  it  appears  in  Sumatra,  Java,  Celebes,  and  more 
commonly  in  New  Guinea  and  the  Bismarck  Archipelago.  It 
has  been  reported  from  Formosa,  but  is  comparatively  rare  in 
the  Philippines. 

Tropical  Africa  is  the  home  of  blackwater  fever.  Here, 
between  the  parallels  of  15°  N.  and  15°  S.,  it  has  been  one 
of  the  deadliest  foes  to  civilization.  On  the  West  Coast  it 
occurs  from  Senegal  to  Damara  Land,  especially  in  Sierra 
Leone,  Gold  Coast,  Nigeria,  Cameroon,  and  the  Congo  region. 
On  the  east  it  prevails  from  Somali  Land  to  Delagoa  Bay,  par- 
ticularly in  British  and  German  East  Africa  and  the  Congo 
Free  State,  and  is  met  with  in  the  Bahr-el-Ghazal  region  and  in 
Sudan.  In  Algeria,  Laveran,11  during  a  residence  of  five 
years,  did  not  observe  a  single  case  and  Brault54  saw  only  one. 
However,  Coste52  has  recently  published  his  observations  of 
25  cases  treated  during  1904-05  in  the  region  of  Arzew.  It 
rages  in  parts  of  Madagascar  and  Reunion,  and  is  known  in 
Mauritius  and  the  Comora  Islands,  notably  Mayotte.  The 
mountainous  islands  of  the  Gulf  of  Guinea  afford  a  few  cases. 


36  THE   STUDY  OF  MALARIA 

Thus  it  is  seen  that,  while  the  peculiar  geographic  distribu- 
tion of  hemoglobinuria  is  embraced  by  that  of  malaria,  it  is 
not  coextensive  with  the  latter.  And  here  the  relation  ceases. 
While  all  localities  in  which  blackwater  fever  exists  endemi- 
cally  are  highly  malarial,  there  are  very  extensive  regions  in 
which  the  severest  forms  of  tropical  malaria  are  rampant 
where  hemoglobinuric  fever  is  unknown. 

It  has  been  attempted  to  explain  the  distribution  by  saying 
that  the  frequency  of  hemoglobinuria  in  a  given  locality  is  in 
direct  ratio  to  the  endemic  index  of  that  locality — that  is,  the 
percentage  of  native-born  children  whose  blood  harbors  mala- 
rial parasites — but  this  explanation  also  presents  difficulties, 
as  the  disease  is  not  present  in  all  localities  whose  endemic 
index  is  high. 

Wellman56  maintains  a  close  relationship  between  the  geo- 
graphical distribution  of  Mysomyia  funesta  in  Angola  and 
that  of  blackwater  fever.  Daniels57  believes  that  if  the  disease 
is  due  to  one  or  all  of  several  varieties  of  mosquitoes  which  he 
mentions,  M.  funestus  must  be  one  of  those  implicated.  F. 
Plehn58  suggested  a  possible  relation  between  the  geographic 
range  of  hemoglobinuric  fever  and  that  of  certain  mosquitoes. 

In  certain  localities  the  disease  seems  to  be  on  the  increase. 
Crosse4  says  that  it  is  increasing  in  certain  parts  of  West 
Africa.  Manson59  refers  to  the  belief  of  competent  observers 
that  it  is  yearly  becoming  more  common  in  Africa.  Johnson60 
and  F.  Plehn61  assert  that  it  is  undoubtedly  becoming  more 
prevalent  on  the  west  coast  of  Africa,  and  A.  Plehn62  believes 
that  it  is  increasing  in  frequency  in  New  Guinea.  The  inhabi- 
tants of  the  region  of  Jalpaiguri,  in  India,  are  recently  said 
to  be  alarmed  at  its  increase  in  that  section.63 

On  the  other  hand,  there  are  places  in  which  it  is  becoming 
less  frequent.  The  medical  report  from  German  East  Africa 
for  the  year  1903-04  shows  a  decrease  from  the  preceding 
year.  The  report  from  Duala  shows  a  steady  annual  decrease 
from  1901  to  1904  inclusive.49  Kohlbrugge7  declares  that  it 
is  becoming  rarer  in  the  Malay  Archipelago.  A.  Plehn,24  after 
mentioning  the  decrease  in  certain  sections  of  West  Africa, 
prophesied  that  in  half  a  century  this  scourge  of  tropical  Africa 


GEOGRAPHIC    DISTRIBUTION  37 

would  become,  if  not  a  historic  reminiscence,  at  least  an  insig- 
nificant rarity.  It  is  probably  becoming  less  frequent  in  some 
of  the  Southern  States. 

Epidemics  of  hemoglobinuric  fever  have  been  described. 
Masterman64  states  that  in  1893  there  was  a  regular  epidemic 
of  malaria  in  and  around  Jaffa,  and  among  the  fatal  cases 
were  a  great  many  of  hemoglobinuria.  Says  Plehn,61  "Not 
infrequently  the  disease  appears  in  epidemic  form,  as  was 
the  case  several  years  ago  in  Goree,  Quittah,  and  Bonny." 
Sambon9  mentions  several  epidemics,  as  follows :  "The  disease 
broke  out  among  the  laborers  employed  in  making  the  canal 
through  the  Isthmus  of  Corinth ;  it  attacked  the  Chinese  labor- 
ers on  the  Congo  Railway;  and  in  1885,  according  to  Dr. 
Wenyon,  of  Fatshan,  China,  it  ravaged,  like  a  plague,  the 
Chinese  army  on  the  Tonquin  border  of  Kwangsi.  In  collec- 
tive dwellings — such  as  barracks,  hospitals,  schools — it  may 
attack  several  persons  at  the  same  time.  In  1885  it  broke  out 
in  a  prison  in  Castiades,  Sardinia,  attacking  24  out  of  800 
convicts." 


CHAPTER  III 

ETIOLOGY 

Depending  as  it  does  for  its  existence  upon  the  life  histories 
of  three  species  of  animals,  malaria  is  of  rather  complex 
etiology.  While  within  the  blood  of  man  the  parasite  is  not 
subject  to  great  variations  of  environment,  no  matter  what  the 
season  or  the  latitude,  nevertheless  exposure  to  cold,  wet 
or  heat,  dietary  or  other  excesses,  will  have  the  effect  of  awak- 
ening latent  malaria. 

But  it  is  the  influence  of  external  factors  upon  the  life  his- 
tory of  the  mosquito  that  determines  the  greatest  variations  in 
the  prevalence  of  malaria  according  to  climate,  season,  tem- 
perature, rainfall,  altitude,  etc. 

Climate. — It  may  be  said,  as  a  general  rule,  that  the  fre- 
quency and  virulence  of  malaria  increase  as  we  approach  the 
equator.  The  conditions  of  warmth  and  moisture  are  more 
propitious  for  the  development  of  parasites  within  the  bodies 
of  mosquitoes  in  tropic  than  in  colder  climates;  this  is  espe- 
cially true  of  the  estivo-autumnal  form  of  the  malarial  parasite. 
Exposure  to  the  heat  of  the  tropical  sun  predisposes  to  the 
cerebral  forms  of  pernicious  malaria,  and  undue  exposure  to 
the  sun's  rays  is  ofttimes  sufficient  to  stimulate  sporulation 
of  the  parasites  of  latent  malaria. 

With  respect  to  latitude  Hirsch18  reached  the  following  con- 
clusions as  to  the  northern  boundary  of  malaria  in  the  northern 
hemisphere.  The  line  starts  from  55°  N.  on  the  western  side 
of  North  America,  sinks  to  45°  on  its  eastern  side,  rises  to 
63°  or  64°  on  the  western  side  of  the  old  world  (Sweden  and 
Finland),  and  runs  across  Northern  Asia  in  about  the  latitude 

oi  55°- 

Long  before  the  discovery  of  the  role  of  the  mosquito  in 
malaria  it  was  known  that  the  disease  was  not  endemic  unless 
the  summer  temperature  maintained  a  certain  average.  Dur- 
ing the  middle  of  the  last  century  Drake85  assumed  that  an 

38 


ETIOLOGY  39 

average  summer  temperature  of  sixty  degrees  is  necessary  to 
the  existence  of  malaria,  and  that  it  will  not  prevail  as  an 
epidemic  where  the  average  temperature  falls  below  sixty-five ; 
also  that  the  fever  will  occur  in  winter  at  all  places  where  that 
season  has  a  mean  temperature  of  sixty  degrees  or  upward. 
Hirsch  maintained  that  the  summer  isobar  of  59°-6o.8°  F. 
marks  the  limit  of  the  occurrence  of  malarial  fever,  and  that 
those  regions  where  the  mean  summer  temperature  does  not 
reach  that  height  are  exempt  from  the  disease.  Curiously 
enough,  it  has  been  recently  repeatedly  demonstrated  that  this 
is  the  lowest  temperature  at  which  the  parasite  will  develop 
in  the  body  of  the  mosquito. 

Season. — While  relapses  may  occur  at  any  season,  and  in 
certain  tropic  regions  fresh  infections  may  occur  during  any 
period  of  the  year,  in  all  temperate  and  most  tropic  regions 
there  are  seasons  during  which  the  disease  is  especially  preva- 
lent. This  is  commonly  known  as  the  malarial  season,  and 
varies  according  to  latitude,  temperature,  rainfall,  soil,  etc. 

The  season  of  primary  attacks  depends  entirely  upon  the 
life  history  of  the  malaria-bearing  mosquitoes.  This  season 
usually  begins  a  few  weeks  after  the  first  brood  of  anophelines 
appears,  which  is  at  the  height  of  summer,  and  continues,  in 
temperate  climates,  until  after  the  nights  become  cool.  In 
each  individual  locality  the  beginning  of  the  season  is  rather 
definite,  the  disease  recurring  at  a  certain  period  each  year 
with  more  or  less  exactitude.  In  most  of  the  regions  of  the 
Southern  States  the  malarial  season  begins  in  the  earlier  half 
of  July.  In  the  latitude  of  Baltimore  the  most  notable  increase 
in  cases  begins  during  August.  The  malarial  season  in  Cali- 
fornia is  from  August  to  October. 

The  following  seasonal  distribution  of  malaria  in  Panama 
is  compiled  from  the  "Reports  of  the  Department  of  Sanita- 
tion of  the  Isthmian  Canal  Commission,"  and  is  the  aggregate 
of  the  three  years,  1906-1908: 

January   4,301  July  6,399 

February  3,624  August  6,319 

March    3,591  September 5,384 

April 2,400  October    5-276 

May 2,127  November 3,814 

June    3,900  December    3,647 


4o 


THE   STUDY  OF  MALARIA 


In  Italy  a  large  number  of  cases   from  various  sources37 
are  distributed  as  follows : 


January   8,567 

February   6,81 1 

March    8,124 

April 9,302 

May 11,101 

June    15,106 


July  41.855 

August    61,335 

September    52,525 

October    35,640 

November    23,298 

December    12,670 


In  Guiana  the  season  of  greatest  prevalence  is  said  to  be 
from  October  to  December  inclusive;  in  St.  Lucia,  W.  I.,  from 
January  to  March;  in  Germany,  from  the  end  of  July  to  the 
middle  of  September;  Holland,  from  the  middle  of  May  to 
middle  of  September;  France,  from  July  to  November;  Bul- 
garia, May  to  October ;  Italy,  from  the  end  of  June  to  Novem- 
ber; Greece,  from  May  to  November;  in  Tonkin,  from  April 
to  November;  Calcutta,  from  October  to  December;  Cyprus, 


tf  f  \v       p  1  Hill      1  ill! Ill  ■liil'i' ' 

j  1 1 ! !  i 1 1 1 1 1 1 1 1 1 1  r  1 1  rrniTfliti  1 1 1 1 U44-1 1 1 1 1 11 1 1 1 1 11  run  n  \  uhm  i  i  i  i  \  1 1 1 1 1 1 1 1  ni 


Fig.  3. — Diagram  showing  relation  between  rainfall  and  malaria  (Plehn). 

Malaria  morbidity. 

.  —  .  —  .  —  .  — .  Rainfall. 
Rainy  days. 

from  July  to  October;  Singapore,  April  to  July;  German 
New  Guinea,  from  November  to  June ;  Northern  Africa,  from 
the  middle  of  June  to  November ;  and  in  German  East  Africa, 
from  April  to  July. 

Where  both  tertian  and  estivo-autumnal  malaria  are  endemic 
the  malarial  season  is  usually  ushered  in  by  cases  of  the  for- 
mer, the  estivo-autumnal  variety  appearing  at  the  height  of 


ETIOLOGY 


41 


the  season.  The  pernicious  forms  of  malaria  occur  with  great- 
est frequence  at  the  height  of  estivo-autumnal  prevalence.  In 
Italy  quartan  malaria  begins  late  in  the  summer  and  continues 
late  in  the  fall.  In  America  this  variety  is  too  infrequent  to 
justify  any  definite  conclusions.  Mixed  and  multiple  infec- 
tions occur  more  frequently  late  in  the  season  than  early. 

Rainfall. — The   influence   of   rainfall   upon   the   extent   of 
malaria  is  very  decided.     Breeding  places  for  mosquitoes  are 


W       tf 


■*  2  o  g  v 


14. 

i     10    mo                    jy\ 

1$-* 

V        _9_       <U                                   jlil       i 

:xu 

J       g       '<*                        -^    4--t^«. 

2:  1  ^ 

±     7      k                 L        T    £  V 

1          ""           ■*" 

*       b       *zli_             L--      -<;--/  .. 

'L         J     ,.         .1     .  +. 

*    *  ■■»  \    zl- 

■\    -*r-- 

7     *     rt        N^     -i               ^t,- 

:/p       4. 

0      i      „.t:  — .«/««., -7        .           T 

X        ft 

»!-.*<                           .      I           M 

-.44     Vh  -C 

/•    •    »*       z  J     r  j  r 

^V            -X7^    4-       - 

s^?        *    _      « 

Fig.  4. — Relation  between  rainfall,  ground  water,  and  malaria  (Ziemann). 


essential  in  the  etiology  of  malaria,  and  limited  pools,  such  as 
result  from  a  fall  of  rain,  are  well  suited  to  the  taste  of  the 
malarial  mosquitoes. 

Rain  has  a  twofold  effect  upon  the  prevalence  of  malaria. 
First,  exposure  to  wet  is  not  infrequently  followed  by  a  recru- 
descence of  a  former  infection.  This  effect  is  usually  imme- 
diate.    Second,  rainfall  produces  breeding  pools  for  the  dis- 


42  THE   STUDY  OF   MALARIA 

seminators  of  malaria.  The  effect  of  fresh  breeding  places 
is  not  shown  immediately.  Allowing  twenty  days  for  the 
aquatic  stages  of  the  mosquito,  ten  days  for  the  mosquito  cycle 
of  the  parasite,  and  a  like  period  for  the  incubative  stage  in 
man,  it  would  be,  obviously,  several  weeks  before  an  increase 
in  malaria  could  be  expected  from  such  a  source.  This  is 
well  exemplified  in  the  tropics,  where  so  much  depends  upon 
rainfall.  Here  the  height  of  the  malaria  curve  is  attained 
toward  the  end  of  the  rainy  season  or  shortly  after. 

A  heavy  rainfall  in  the  spring  and  early  summer  has  long 
had  the  reputation  of  being  favorable  to  the  spread  of  malaria. 

While  rainfall  is  essential  to  the  development  of  malaria, 
if  excessive  it  may  have  the  opposite  effect  by  scouring  breed- 
ing pools  and  destroying  the  contained  ova  and  young  of  the 
mosquito.  Moderate  rains  at  short  intervals  are  more  produc- 
tive of  breeding  pools  than  heavy  downpours  at  long  intervals. 
Hence,  the  number  of  rainy  days,  as  well  as  the  actual  rainfall 
in  inches,  is  a  factor  in  the  etiology  of  malaria. 

In  very  low  countries  rainy  years  may  be  healthy  years. 
This  is  said  to  be  the  case  in  the  Netherlands.66 

Dew  and  a  high  atmospheric  moisture  were  formerly  accred- 
ited with  being  factors  in  the  cause  of  malaria.  This  was 
doubtless  on  account  of  the  well-recognized  danger  of  con- 
tracting malaria  between  sunset  and  sunrise.  Other  than  as 
an  index  of  ground-moisture  it  is  doubtful  whether  atmos- 
pheric moisture  bears  any  relation  to  primary  infections  with 
malaria. 

Soil. — The  chemical  composition  of  the  soil  has  an  effect 
upon  the  reign  of  malaria  only  so  far  as  the  relation  of  the 
soil  to  the  retention  of  water  is  concerned.  More  depends 
upon  the  physical  conformation  than  upon  the  geologic  char- 
acteristics of  the  soil.  As  a  rule,  clay  soils  retain  moisture 
better  than  the  sandy,  though  there  are  exceptions.  Rocky 
regions  are  less  apt  to  harbor  breeding  pools  because  of  good 
drainage,  but  pools  upon  a  rock-bed  are  very  persistent.  The 
soil  must  be  of  such  a  character  as  to  retain  surface  water 
sufficiently  long  for  the  aquatic  stages  of  mosquito  life  to  be 
completed. 


ETIOLOGY  43 

More  depends  upon  the  nature  of  the  subsoil  than  that  of 
the  surface  soil.  Even  where  the  surface  soil  is  very  porous, 
an  impervious  subsoil  favors  the  accumulation  of  surface  water 
by  preventing  further  percolation.  Thus  the  height  of  the 
ground  water  during  the  malarial  season  bears  a  close  relation 
to  the  volume  of  the  malarial  endemic.  Proximity  to  col- 
lections of  water,  by  raising  the  height  of  the  ground  water, 
favors  the  development  of  malaria. 

Topography. — In  countries  designated  malarial,  regions  en- 
tirely free  from  the  disease  are  not  uncommon.  In  a  region 
within  a  short  distance  of  a  severely  scourged  locality  malaria 
may  be  entirely  absent.  The  difference  in  the  prevalence  of 
malaria  within  limited  areas  is  dependent,  in  great  measure, 
upon  the  physical  characteristics  of  the  surface  of  the  land. 

It  has  been  known  for  centuries  that  malaria  is  partial  to 
low  marshy  places,  swamps,  lakesides,  low  coast  levels,  and 
river  valleys,  and  especially  the  deltas  of  large  rivers.  The 
cleaner  the  banks  and  the  swifter  the  current  of  the  streams 
at  all  stages  the  less  apt  they  are  to  be  malarious.  Streams 
with  sluggish  or  no  currents,  and  with  weedy  banks  which 
foster  eddies,  are  breeding  places  for  mosquitoes. 

Nearly  two  hundred  years  ago  Lancisi67  described  noxious 
and  harmless  swamps.  His  description  of  the  former  depicts 
well  the  favorite  breeding  places  of  the  malaria-bearing  mos- 
quitoes. 

Drake65  well  describes  the  topography  of  the  malarial  region 
of  the  United  States  as  follows: 

"In  the  maritime  parts  of  Florida,  Alabama,  Mississippi, 
Louisiana,  and  Texas  surface  water  is  abundant,  for  one  side 
of  each  rests  on  the  Gulf,  which  has  many  inlets  and  little 
bays,  the  banks  of  which  are  inhabited.  The  rivers,  more- 
over, are  numerous,  and  as  they  approach  the  Gulf  expand 
into  broad  estuaries  or  deltas.  The  delta  of  the  Mississippi 
abounds  in  lakes,  lagoons,  and  bayous.  As  we  ascend  this 
and  the  smaller  rivers  wide  cypress  and  liquid-amber  swamps, 
annually  replenished,  skirt  both  sides.  The  intervening  plains 
are  cut  up  by  smaller  streams,  which  have  wide  alluvions, 
often  subjected  to  inundations,  and  the  country  between  them 


44  THE   STUDY   OF   MALARIA 

abounds  in  swamps,  from  which  even  the  sandy  pine-plateaus 
are  not  entirely  free.  This  continues  to  be  their  condition 
till  we  reach  the  flanks  of  the  Cumberland  Mountains  on  the 
east  and  those  of  the  Ozark  Hills  to  the  west.  As  we  ascend 
the  Mississippi  to  the  mouth  of  the  Missouri  we  find  its  annual 
floods  leaving  small  lakes,  ponds,  swamps,  and  lagoons,  which 
in  the  aggregate  are  of  great  extent  and  but  partially  drained 
or  dried  up  before  the  next  inundation.  Now,  as  we  have 
seen,  the  whole  of  this  region  is  infested  with  autumnal  fever 
beyond  any  other  portion  of  the  valley. 

"In  North  Alabama,  Tennessee,  and  Kentucky  swamps  are 
almost  unknown,  except  along  the  few  rivers  which  have  wide 
bottom  lands,  most  of  which,  moreover,  are  exempt  from 
inundation.  The  rivers,  however,  are  sinuous,  and  in  summer 
sluggish  and  pondy,  and  it  is  in  their  vicinity  chiefly  that 
autumnal  fever  prevails.  In  the  States  of  Illinois,  Indiana, 
and  Ohio  the  rivers  generally  flow  through  wide  valleys,  many 
of  which  are  liable  to  be  overflowed.  Small  lakes,  ponds,  and 
swamps  are  also  frequent  in  certain  portions  of  these  States, 
and  it  is  precisely  these  localities  which  are  most  infested.  To 
the  east  of  all  the  States  mentioned,  as  we  climb  the  moun- 
tains, the  surface  water  is  no  longer  found  in  basins,  and  the 
streams  generally  have  a  rapid  current,  down  narrow  and 
rocky  channels,  and  here  autumnal  fever  nearly  disappears, 
or  when  present  is  confined  to  the  valley  of  some  stagnating 
stream.  Everywhere  west  of  the  States  of  Arkansas,  Missouri, 
and  Iowa  surface  water  is  scarce,  the  declivity  of  the  plain 
which  stretches  from  the  Rocky  Mountains  favoring  its  escape, 
while  the  subjacent  sand  almost  absorbs  even  considerable 
rivers.  Thus,  as  we  advance  into  that  desert,  we  come  at 
the  same  time  to  the  limits  of  the  surface  water  and  of  aut- 
umnal fever.  In  the  North  there  is  no  deficiency,  for  the 
whole  country  is  essentially  lacustrine,  and  up  to  a  certain 
latitude  the  fever  prevails.  Thus  the  shores  of  Lake  Ontario 
and  Lake  Erie,  with  those  of  the  southern  extremity  of  Huron 
and  Michigan,  are  infested,  and  suffer  far  more  than  the  dry 
lands  which  surround  them.  But  beyond  these  limits,  on  the 
shores  of  the  two  latter  lakes  and  on  those  of  Lake  Superior, 


ETIOLOGY  45 

the  fever,  as  we  have  seen,  is  never  epidemic,  although  water 
is  abundant;  and  still  further  North,  where  small  lakes  and 
their  connecting  streams  exist  in  countless  numbers,  the  disease 
is  unknown,  showing  that,  while  water  is  essential  to  the  pro- 
duction of  this  fever,  other  causes  must  cooperate  to  give  it 
power." 

Canals,  dams,  stock,  and  other  ponds,  railroad  and  levee 
borrow  pits  and  other  collections  of  water,  particularly  when 
stagnant,  often  breed  anopheline  larvae,  hence  favoring  the 
development  of  paludism. 

It  is  generally  believed  that  salt  marshes  are  never  malari- 
ous, and  that  anopheles  larvae  cannot  develop  in  sea-water. 
This  is,  however,  not  strictly  true.  DeVogel68  has  recently 
shown  that  anopheles  larvse  may  develop  in  sea-water  evapo- 
rated to  half  its  initial  volume,  and  a  number  of  other  observ- 
ers have  found  larvae  in  salt  water.  But  marshes  of  pure 
sea-water  are  not  nearly  so  noxious  as  those  of  brackish  water, 
a  mixture  of  salt  and  fresh  water,  which  are  famous  anopheles 
breeders.  It  appears  that  in  some  instances  where  salt  water 
is  inimical  to  the  development  of  the  aquatic  stages  of  mos- 
quitoes they  may  gradually  become  accustomed  to  the  environ- 
ment. 

Altitude. — Malaria  is  essentially  a  disease  of  the  low  lands, 
high  altitude  being  relatively  exempt.  This  is  partially  ac- 
counted for  by  the  better  drainage  of  elevated  altitudes  and 
fewer  pools  in  which  malarial  mosquitoes  may  breed.  The 
lower  temperature  of  high  altitudes  is  also  a  factor  in  main- 
taining a  low  malarial  morbidity  in  these  regions. 

It  is  known  that  anopheline  mosquitoes  do  not  fly  to  great 
heights.  Hence  sleeping  in  an  upper  story  or  in  a  building 
situated  high  above  the  ground  gives  a  measure  of  protection 
from  malaria.  Laborers  employed  in  highly  malarial  sections, 
and  who  sleep  in  the  surrounding  hills,  even  of  moderate  alti- 
tude, often  remain  entirely  free  from  infection. 

A  few  hundred  feet  in  altitude  may  show  a  more  marked 
difference  in  the  prevalence  of  malaria  than  as  many  miles 
in  latitude. 

The  general  rule  that  malaria  is  a  disease  of  low  countries 


46  THE   STUDY   OF   MALARIA 

has  some  exceptions.  This  is  especially  true  in  the  tropics, 
where  the  disease  may  be  encountered  at  very  high  altitudes. 
It  may  be  said  that  the  altitude  at  which  malaria  may  occur 
varies  in  inverse  ratio  to  latitude. 

Malaria  has  been  found  on  Lake  Nyssa  at  an  altitude  of 
1,560  metres;  at  Colico,  2,500  metres;  in  the  Himalaya  Moun- 
tains, at  2,000  metres;  in  the  Andes,  at  2,500  metres;  at  Blan- 
tyre,  at  3,000  feet;  German  East  Africa,  at  1,550  metres;  at 
points  in  Central  Africa,  at  heights  of  over  5,000  feet;  and 
in  some  of  the  high-lying  valleys  of  Syria,  at  altitudes  of 
1,200  metres. 

Some  of  the  cases  in  high  altitudes  reported  as  malaria  may 
be  mistakes  in  diagnosis;  other  cases  may  be  malaria  con- 
tracted in  the  lowlands.  Thus  Tosari,  at  an  elevation  of  1,777 
metres,  had  been  cited  as  a  place  where  malaria  prevailed  with- 
out the  presence  of  mosquitoes,  and  this  was  used  as  an  argu- 
ment against  the  "mosquito  theory."  Koch,69  investigating 
the  place  in  1899,  examined  the  blood  of  eighty-two  children; 
in  none  was  the  parasite  of  malaria  detected.  The  only  case 
of  malaria  found  was  in  a  man  who,  twelve  days  before  the 
beginning  of  his  illness,  had  spent  the  night  in  a  highly  mala- 
rial place  upon  the  coast. 

However,  malaria  is  endemic  in  certain  places  of  high  alti- 
tude. Such  are  Eritrea,  in  altitudes  of  1,750  metres;  Upper 
Tonkin,  at  1,000  metres ;  parts  of  Madagascar,  at  1,100  metres ; 
parts  of  Reunion  Island,  1,200  metres;  in  Java,  at  1,000 
metres;  and  in  the  Philippines  it  is  said  that,  while  certain 
valleys  are  almost  free  from  malaria,  the  hills  in  the  vicinity 
are  notoriously  infected.70  Wright,38  in  British  Malaya,  found 
anopheles  larvae  in  pools  at  an  elevation  of  2,300  feet. 

Earthquakes  and  volcanic  eruptions  have  been  followed  by 
a  great  development  of  malaria.  Examples  are  cited  of  Rome 
in  1703,  in  Reggio  in  1783,  and  Palermo  in  1828.  Remark- 
able instances  have  occurred  in  Peru  also.  The  most  recent 
illustration  is  that  of  Amboina,  in  the  East  Indies,  which  had 
until  1835  been  remarkably  free  from  malaria.  In  that  year 
a  severe  earthquake  occurred,  and  since  then  the  malaria  has 
increased  both  in  extent  and  intensity.18 


ETIOLOGY  47 

Such  results  can  be  explained  only  by  an  increase  of  stagnant 
water  following  these  violent  disturbances,  probably  through 
the  interruption  of  the  flow  of  ground-water. 

Inundations. — Since  very  early  times  overflows  have  been 
recognized  as  a  prolific  cause  of  epidemics  of  malaria.  Tacitus, 
Suetonious,  Livy,  Dionysius,  Cassio,  and  Strabo  mention  such 
results  from  inundations  of  the  Tiber.  This  stream  experi- 
enced an  overflow  in  1695,  which  was  described  by  Lancisi. 
The  water  covered  a  broad  area  of  country,  filling  ditches, 
sewers,  and  canals.  The  following  June,  July,  and  August 
were  extremely  hot.  An  epidemic  of  malignant  malarial  fever 
ensued  and,  spreading  far  and  wide,  occasioned  a  great  mor- 
tality. 

In  giving  a  description  of  a  trip  up  the  Tigris  River,  Lind71 
gives  the  following  account  of  a  curious  strategem:  "Here 
we  were  informed  that  the  Arabs  had  broken  down  the  banks 
of  the  river  near  Bassora,  with  a  design  to  cover  with  water 
the  deserts  in  its  neighborhood.  This,  it  seems,  is  the  usual 
method  of  revenge  taken  by  the  Arabs  for  any  injury  done 
them  by  the  Turks  in  Bassora,  and  it  was  represented  to  us 
as  an  act  of  the  most  shocking  barbarity,  since  a  general  con- 
suming sickness  would  undoubtedly  be  the  consequence.  This 
was  the  case  fifteen  years  before,  when  the  Arabs,  by  demol- 
ishing the  banks  of  this  river,  laid  the  environs  of  Bassora 
under  water.  The  stagnating  and  putrid  water  in  the  adjacent 
country  and  the  great  quantity  of  dead  and  corrupted  fish  at 
that  time  lying  upon  the  shore  polluted  the  whole  atmosphere 
and  produced  a  putrid  and  mortal  fever.  Of  this  fever  be- 
tween 12,000  and  14,000  of  the  inhabitants  died;  at  the  same 
time  not  above  two  or  three  of  the  Europeans  who  were  set- 
tled there  escaped  with  life." 

Epidemics  of  malaria  following  overflows  of  the  Nile, 
Ganges,  Indus,  Euphrates,  Niger,  Senegal,  Volga,  Danube, 
Saone,  Rhone,  Loire,  Mississippi,  and  other  rivers  have  been 
described. 

The  immediate  effect  of  an  inundation  is  to  check  the  devel- 
opment of  malaria.  This  is  a  result  of  a  destructive  effect  of 
the  flood  upon  the  breeding  pools  of  mosquitoes.     It  is  only 


48  THE   STUDY   OF   MALARIA 

after  the  waters  have  subsided  and  pools  and  marshes  are 
left  that  the  epidemic  develops. 

Trees  and  Vegetation. — It  was  formerly  believed  that, 
while  decaying  vegetation  was  the  cause  of  malaria,  living 
plant  life  greatly  retarded  its  development.  Whole  volumes 
have  been  devoted  to  this  subject.  It  was  supposed  that  vege- 
tation filtered  the  miasm  from  the  air.  It  was  argued  that  if 
air  vitiated  by  respiration  be  confined  in  a  bottle  containing 
a  living  plant  and  exposed  to  the  rays  of  the  sun,  the  carbonic- 
acid  gas  will  be  absorbed  and  the  air  restored  to  its  original 
condition,  plant  life  consuming  carbon  dioxide  and  exhaling 
oxygen.  So  firm  was  this  belief  that  in  the  days  of  ancient 
Rome  trees  were  protected  by  law. 

It  is  needless  to  say  that  the  protective  power  of  living 
plants  was  as  much  overestimated  as  the  faculty  of  decaying 
vegetation  to  cause  malaria.  Their  power  of  absorbing  moist- 
ure from  the  soil  is  more  than  outweighed  by  the  shade  they 
afford  the  ground. 

While  the  clearing  of  land  of  trees  and  vegetation  may  be 
followed  by  an  outbreak  of  malaria,  this  may  be  due  to  the 
overturning  of  the  soil,  which  usually  goes  hand  in  hand  with 
opening  land,  and  to  the  hardships  attending  such  labor.  The 
ultimate  effect  of  clearing  trees  from  the  land  is  to  diminish 
malaria  by  permitting  the  sun  to  dry  the  soil. 

If  trees  have  any  protective  virtue  whatever  it  is  probably 
through  affording  shelter  and  food  for  mosquitoes.  The  cul- 
ture of  eucalyptus  trees  is  now  known  to  have  no  prophylactic 
effect  upon  malaria. 

Weeds  and  other  vegetation  growing  in  the  water  favor 
the  development  of  mosquito  larvae  by  protecting  the  surface 
of  the  water  from  agitation  by  the  wind. 

Vegetable  decomposition  bears  no  relation  to  the  etiology 
of  malaria  other  than  as  an  index  to  heat  and  moisture. 

Wind. — The  wind  was  formerly  held  responsible  for  trans- 
mitting malaria  long  distances.  It  was  believed  that  the  mala- 
ria of  Edinburgh  was  imported  by  the  winds  from  Holland, 
and  that  Italy  became  malarious  through  the  agency  of  the 
African  sirocco.     The  land  breezes,   especially  if  they  blew 


ETIOLOGY 


49 


over  marshy  areas,  were  regarded  as  more  highly  noxious 
than  the  sea  breezes. 

As  a  matter  of  fact,  the  wind  has  little  or  no  power  to 
transmit  malaria  for  distances  of  any  consequence.  While 
it  is  theoretically  possible  for  infected  mosquitoes  to  be  borne 
by  the  wind,  in  reality  these  insects,  especially  the  anopheles, 
being  weak  fliers,  seek  shelter  while  a  breeze  is  blowing. 
The  immunity  from  mosquito  bites  afforded  by  the  Indian 
punkah,  or  a  common  fan,  is  evidence  of  this. 

Furthermore,  the  disturbing  effect  of  the  wind  upon  the 
surface  of  the  water  interferes  with  oviposition  of  the  adults 
and  with  respiration  of  larvse  and  pupae. 

Exposure  to  cold  winds  may  have  the  effect  of  arousing 
latent  malaria.  An  incident  related  by  Watson72  is  a  striking 
illustration.  Thirty  ladies  and  gentlemen  had  sailed  to  the 
mouth  of  the  Tiber  on  an  excursion  of  pleasure.  Suddenly 
the  breeze  shifted  to  the  south  and  began  to  blow  over  a 
marshy  tract  of  land  situated  to  windward  of  them.  Twenty- 
nine  of  the  thirty  were  immediately  after  attacked  with  tertian 
ague. 

The  occurrence  of  malaria  upon  shipboard  has  been  cited 
as  an  argument  that  malaria  is  an  air-borne  disease.  Bilge 
water  in  the  holds  of  vessels  has  also  been  accredited  with 
producing  malaria  at  sea.  The  dangers  of  malaria  from  car- 
goes of  sugar  and  fruits  were  recognized  by  old  writers. 

Malaria  occurring  upon  ships  may  be  accounted  for  in  sev- 
eral ways.  These  cases  may  be  manifestations  of  malaria 
contracted  upon  shore.  Even  cases  occurring  long  after  em- 
barking may  be  explosions  of  latent  malaria.  If  vessels  anchor 
too  close  inshore  in  malarial  regions  infected  mosquitoes  may 
easily  gain  access  to  the  crew — a  half  mile  from  shore  is 
probably  a  safe  distance.  It  has  been  proven  that  mosquitoes 
may  be  carried  for  considerable  periods  in  the  holds  and  sleep- 
ing apartments  of  ships. 

Commercial  vessels  are  more  apt  to  carry  mosquitoes  than 
are  warships,  through  loading  and  unloading  of  cargoes. 

There  are  many  places  where,  notwithstanding  apparently 
favorable  topographic  and  meteorologic  conditions,  malaria  is 


50  THE   STUDY   OF  MALARIA 

entirely  absent.  This  is  due  to  the  absence  of  either  malaria- 
bearing  mosquitoes,  or  malarial  parasites,  or  of  both.  Among 
a  number  of  such  places  may  be  mentioned  the  city  of  Rome 
and  other  portions  of  Italy,  Madeira,  portions  of  Cameroon, 
Chole  Island,  Comoro  Island,  Rodriquez  Island,  the  Sey- 
chelles Islands,  portions  of  India  and  of  Borneo,  the  French 
Islands,  Ponape,  Saipan,  Samoa,  New  Caledonia,  Tahiti,  Bar- 
badoes,  and  portions  of  Brazil  and  of  the  Argentine  Republic. 
The  majority  of  such  localities  are  islands  and  in  the  southern 
hemisphere. 

Race ;  Immunity. — Certain  protozoan  diseases  among  lower 
animals  confer  immunity.  In  the  Texas  fever  of  cattle  an 
attack,  if  recovered  from,  is  followed  by  immunity.  There 
are  said  to  be  breeds  of  cattle  naturally  immune  to  the  disease. 
In  the  large  game  animals  of  Africa  one  infection  with  try- 
panosoma  brucei  confers  immunity.  Koch  found  that  birds 
that  had  been  infected  with  proteosoma  grassii  could  not  be  re- 
infected. 

From  analogy  it  might  therefore  be  expected  that  immunity 
to  malaria  might  exist  with  some  individuals  or  races.  This 
is  true,  however,  in  only  a  limited  sense. 

While  the  various  races  of  mankind  vary  somewhat  in  sus- 
ceptibility to  malaria  none  can  be  said  to  possess  absolute 
immunity. 

Caucasians  residing  in  non-malarial  countries  are,  when 
exposed,  most  liable  to  contract  malaria.  Negroes  bred  in 
highly  malarial  regions  are,  as  long  as  they  remain  upon  the 
native  soil,  least  susceptible  to  paludal  infection. 

Immunity  within  the  race  increases  generally  as  we  go  to- 
ward the  equator.  Thus  the  negroes  of  the  Southern  States 
display  less  immunity  than  the  negroes  of  the  West  Indies  or 
of  tropic  Africa.  Likewise  it  may  be  said  that  immunity  is 
much  more  marked  in  countries  with  a  high  than  in  those 
with  a  low,  endemic  index. 

The  immunity  of  the  negro  race  has  been  variously  esti- 
mated, some  observers  maintaining  that  they  are  absolutely 
proof  against  malarial  invasion,  while  others  hold  that  they 
are  as  susceptible  as  the  whites.     The  truth  lies  between  these 


ETIOLOGY  51 

two  extremes.  Adult  negroes  reared  in  malarial  regions  are 
much  less  liable  to  paludism,  as  long  as  they  remain  indigenous, 
than  are  the  whites.  The  negro  race  does  not,  however,  enjoy 
an  absolute  but  only  a  relative  immunity  from  malaria. 

According  to  Sternberg,73  there  were  in  the  Department  of 
Texas  of  the  United  States  Army  during  the  year  ending  June 
30,  1883,  among  the  white  soldiers  21.36  per  cent.;  colored, 
6.27  per  cent.,  of  periodic  fevers  to  all  kinds  of  fevers. 

In  1845  m°st  of  the  Europeans  aboard  the  steamer  L'Eclair, 
stationed  upon  the  coast  of  Africa,  died  of  malarial  fever, 
while  none  of  the  forty  Kroo  negroes  who  were  members  of 
the  crew  were  attacked. 

In  the  hospitals  of  St.  Louis  and  of  Goree,  among  100  Euro- 
pean patients  36  have  malaria,  while  of  100  black  patients 
only  9  have  malaria.1 

The  medical  statistics  of  the  French  colonial  troops  for  the 
year  1903  give  the  following  figures  for  French  West  Africa: 
European  troops,  malarial  morbidity,  690;  mortality,  7.5  per 
thousand  of  effective  force;  negro  troops,  malarial  morbidity, 
12.45  >  mortality,  0.3  per  thousand. 

The  following  table  from  La  Roche74  will  show  the  com- 
parative ratio  of  mortality  from  the  disease  per  thousand  of 
mean  strength  in  various  commands  of  the  British  Army: 

Whites.  Blacks. 

Windward  and  Leeward  Islands 36.9  4.6 

Jamaica    101.9  8.2 

Bahamas    IS9-I  5-6 

Honduras    81.0  4.4 

Sierra    Leone 410.2  2.4 

Mauritius  1.7  0.0 

Ceylon    25.7  1.1 

Sternberg73  gives  the  ratio  per  thousand  of  mortality  from 
malarial  diseases  in  the  United  States  Army  thus : 

1868.  1869.  1870. 

White    94.20  140.67  72.99 

Colored   74.62  15.62  38.46 

From  a  compilation  of  the  mortality  statistics  for  the  years 
1852-1866  in  Guiana,  Maurel75  gives  the  following  results: 

Number  of  Deaths.  Ratio. 

Europeans   12,819  12.00 

Arabs    1,1X2  8.54 

Negroes    i,i72  5-75 


52  THE   STUDY   OF  MALARIA 

According  to  Hirsch,18  there  died  of  malarial  fevers  per 

thousand  of  population  in  Ceylon : 

Xegroes    „ i.i 

Indians    4.5 

Malays  6.7 

Singalese 7.0 

English    24.6 

During  the  Civil  War  both  the  morbidity  and  mortality 
from  malaria  in  the  negro  race  were  greater  than  in  the  white 
race.  However,  the  negro  soldiers  are  said  to  have  been 
more  exposed  to  malaria  than  the  whites,  having  been  aggre- 
gated in  malarial  localities.76 

With  the  better  hygienic  surroundings  and  more  limited 
exposure  of  the  whites  the  negroes  would  probably  be  attacked 
less  often  than  they  are.  Whether  the  color,  thickness,  or 
other  qualities  of  the  skin  of  this  race  have  anything  to  do 
with  their  relative  immunity  is  not  known. 

The  Chinese  are  said  to  be  very  susceptible  to  malarial 
infection.  The  Arabians  and  the  Siamese  are  almost  as  fre- 
quently and  as  gravely  attacked  as  the  Europeans. 

Laveran1  states  that  it  is  difficult  to  estimate  exactly  the 
relative  frequence  of  malarial  fevers  in  the  Europeans  and  in 
the  Algerians,  since  the  latter  often  escape  observation,  but 
he  believes  the  natives  have  a  degree  of  resistance  and  of 
tolerance  not  possessed  by  the  Europeans. 

The  disease  is  said  to  be  relatively  rare  in  the  natives  of 
Madagascar.  Adult  Filipinos  are  more  frequently  attacked 
than  the  African  negroes.  The  Abyssinians  are  often  in- 
fected. The  Malays,  Javanese,  and  Tamils  are  much  less 
susceptible  than  the  Caucasians. 

At  Stephansort  Koch42  found  various  races  infected  in  the 
following  proportions : 

Number  of  Per-     Number  infected      p      (---«. 
sons  Examined.        with  Malaria.  <-eni. 

Europeans    21  12  57.1 

Chinese    240  63  26.3 

Malays   209  53  25.3 

Melanesians    264  29  10.9 

Total    ~734  "i57  214 

Immunity  from  malaria  is  probably  an  acquired  immunity 
in  the  great  majority  of  instances,  though  the  contrary  opinion 


ETIOLOGY 


53 


is  held  by  some  competent  authorities  upon  the  subject.  The 
reasons  for  believing  that  this  immunity  is  acquired  by  re- 
peated infection,  especially  in  childhood,  and  by  prolonged 
residence  in  a  malarial  region,  a  sort  of  acclimatization,  are 
that  immunity  is  much  more  prevalent  in  adults  than  in  chil- 
dren; that  immunity  is  often  diminished  by  a  change  of  resi- 
dence, or  may  be  entirely  lost  by  a  temporary  residence  in  a 
non-malarial  climate;  and  that  immunity  in  an  individual  may 
exist  toward  one  form  of  malaria  and  not  toward  others. 

That  immunity  is  much  more  manifest  in  adults  than  in 
children  is  evident  from  the  consideration  of  the  endemic 
index  of  a  malarial  region,  particularly  of  countries  where  the 
latter  is  high.  During  the  first  years  of  life  many  individuals 
examined  show  evidence  of  malarial  infection,  older  children 
in  a  less  proportion,  and  adults  evince  a  relative  immunity. 
This  would  hardly  be  the  case  if  the  immunity  were  racial 
and  congenital. 

The  effect  of  a  change  of  residence  upon  malarial  immunity 
is  a  well-known  fact.  Plehn5  says  that  the  Soudan  negroes, 
relatively  immune  at  home,  are  often  afflicted  with  malaria 
when  going  as  soldiers  to  other  parts  of  the  continent.  Smith77 
states  that,  while  the  native  negroes  of  Sierra  Leone  are  in- 
frequently attacked,  and  only  with  mild  degrees  of  malaria, 
in  the  West  Indies  regiment  of  negroes  stationed  in  Sierra 
Leone  the  fever  is  of  a  very  severe  and  often  fatal  character. 

Individuals  once  immune  to  malaria  may  become  susceptible 
on  returning  home  from  a  temporary  residence  in  a  malaria- 
free  country.  Plehn5  mentions  three  Cameroon  negroes  who, 
shortly  after  returning  from  a  several  years'  sojourn  in  Eu- 
rope, were  attacked  with  severe  remittent  fever. 

Repeated  infection  and  consequent  immunity  to  one  form 
of  malaria  does  not  usually  protect  the  individual  from  the 
other  forms.  Koch78  found  certain  islands  among  the  Bis- 
marck Archipelago  where  quartan  fever  alone  was  endemic. 
Laborers  from  these  islands  sickened  readily  with  tertian  and 
estivo-autumnal  malaria  in  Stephensort.  Elting79  has  shown 
that  persons  who  could  not  be  artificially  inoculated  with  a 
certain  variety  of  the  parasite  could  be  with  another. 


54  TEE   STUDY  OF   MALARIA 

In  the  South  there  is  little  difference  between  the  races  as 
regards  susceptibility  to  the  various  forms  of  malarial  infec- 
tion— tertian,  quartan,  and  estivo-autumnal.  Clinically,  how- 
ever, pernicious  cases,  cachexia  and  hemoglobinuric  fever,  are 
rarer  in  the  negro. 

Instances  of  cachexia  followed  by  immunity  have  been  ob- 
served, especially  by  the  Italian  school.  In  these  cases,  after 
recession  of  the  spleen  and  liver,  and  restoration  of  the  blood 
elements,  a  stable  immunity  resulted.  Subjects  of  existing 
cachexia,  even  though  free  from  clinic  evidences  of  acute 
malaria  for  years,  can  hardly  be  regarded  as  immune. 

Rarely  are  persons  encountered  in  highly  malarial  localities 
who  have  never  been  attacked  with  malaria.  Such  persons  are 
supposed  to  possess  congenital  immunity.  Celli80  obtained  pre- 
cise histories  of  four  persons  living  in  the  Pontine  Marshes 
who  were  absolutely  immune,  having  never  had  malaria, 
though  they  took  no  prophylactic  precautions ;  their  color  was 
good,  and  their  livers  and  spleens  normal.  In  persons  claim- 
ing never  to  have  had  malaria  allowances  must  be  made  for 
the  possibility  of  unrecognized  attacks,  especially  in  early  child- 
hood, which  might  give  rise  to  an  acquired  immunity. 

In  conclusion,  the  resistance  of  the  black  race  to  malaria 
is  due  to  repeated  attacks  in  early  childhood,  and  not  to  any- 
great  extent  to  heredity.  While  in  a  sense  natural  selection 
is  a  factor,  it  is  largely  an  individual  struggle,  the  selection 
of  the  fittest  occurring  in  infancy,  and  but  little  being  derived 
from  progenitors. 

Sex. — As  a  general  rule,  females  are  less  often  attacked 
with  malaria  than  males,  though  in  childhood  the  proportion 
is  about  even. 

That  women  are  less  frequently  infected  is  not  due  to  a 
higher  degree  of  resistance,  but  to  the  fact  that  they  are  less 
often  exposed  and  are  more  temperate  in  their  habits.  It  is 
probable  that  if  they  were  equally  exposed  with  males  they 
would  be  even  more  often  infected  than  the  latter,  on  account 
of  the  greater  delicacy  of  the  skin  and  the  manner  of  dress. 

In  certain  localities  women  are  not  less  frequently  attacked 
than  men.     In  Panama  there  is  said  to  be  very  little,  if  any, 


ETIOLOGY  55 

difference  between  the  sexes  in  this  respect.30  In  the  Dutch 
East  Indies  European  women  are  more  susceptible  than  men.81 
Davidson66  says  that  from  1871-75  the  death  rate  of  soldiers' 
wives  in  India  was  4.20  per  thousand,  as  compared  with  2.81 
for  the  men;  and  that  in  Bombay,  1885-86,  the  female  death 
rate  was  10.14;  that  of  males,  7.56. 

The  following  are  some  figures  showing  the  sex  distribution 
in  a  few  localities : 

Males.  Females. 

Stephansort42  32                 21 

Alabama74    585               451 

Italy82    312               327 

Italy83    311               236 

Bulgaria36 1,742               995 

Italy84    268               147 

Greece68    1,202               972 

Baltimore29    493               121 

Total  , 4,945  3,270 

In  an  institution  in  Alabama  Simms  and  Warwick85  found 
among  deaf  mutes  1.05  per  cent,  of  the  males  and  6  per  cent, 
of  the  females  infected ;  among  blind,  6  per  cent,  of  the  males 
and  3  per  cent,  of  the  females. 

Pregnant  women  are  probably  less  often  infected  because, 
on  account  of  their  condition,  they  are  less  often  exposed; 
when  exposed  they  are  very  susceptible.  The  puerperium  pre- 
disposes to  malaria. 

Age. — Children  are  more  frequently  and  more  severely  af- 
flicted with  malaria  than  adults.  This  is  probably  due  to  their 
more  delicate  skin,  their  manner  of  dress,  sounder  and  more 
prolonged  sleep,  and  inability  to  defend  themselves  against 
mosquito  bites.  The  fact  that  cases  of  malaria  in  children 
more  often  escape  correct  diagnosis  may  account  somewhat 
for  the  greater  frequency,  especially  of  relapses. 

The  subjoined  figures  show  the  distribution  of  malaria 
according  to  age : 

Age  0-10     10-20      20-30      30-40     40-50      50-60      60-70     70-80     80-90 

Thayer   and   Hewet- 

son29 18  146  204  130  65        36        11          3          1 

Rogers80    2  13  10  3       

Cardamatis68  729  499  398  230  144      100        55         15          3 

Conti82  J24S  146  83  _6i  _6i>     _^_     _^_     ^^     ^! 

Total  994  804  695  424  272       136        66        18          4 


56 


THE   STUDY   OF   MALARIA 


Of  2,073  malarial  subjects  observed  by  De  Brun86  at  Beirut 
1,065  were  children  and  under  eight  years  of  age. 

Of  1,784  cases  recorded  by  Hope,40  862  were  in  children 
under  fifteen  and  922  in  persons  of  fifteen  or  over. 

Malaria  causes  a  greater  number  of  deaths  in  children  than 
among  adults.  Strachan87  tabulates  2,377  deaths  from  malaria, 
of  which  1,428  occurred  in  children  under  one  year  of  age, 
275  from  one  to  five  years  of  age,  157  from  five  to  twenty, 
and  517  from  twenty  to  seventy-five  years  of  age. 

The  following  figures  show  the  percentage  mortality  of 
malaria,  according  to  age,  compiled  from  the  table  of  Savas68 
in  Greece: 


0-5  Years. 

54 


5-10  Years. 
10 


10-20  Years. 


20-40  Years. 
II 


40-60  Years. 
9 


60-80  Years. 


Endemic  Index. — The  percentage  of  children  infected  in  a 
given  locality  is  the  index  to  the  prevalence  of  malaria  in  that 
region  (Fig.  5).     As  Ross88  expresses  it,  "There  is  probably 


Fig.  6. — Spleen  rate  in  British  Central  Africa  (after  Daniels). 

only  one  really  accurate  method  by  which  we  can  determine 
the  degree  of  malaria  in  a  given  locality,  and  that  is  by  ascer- 
taining the  average  time  in  which  a  newcomer  becomes  in- 
fected.    The  shorter  this  period  the  greater,   evidently,  the 


Fig.  5. — This  group  shows  a  high  Index  endemicus. 


ETIOLOGY  57 

malaria  potential  of  the  locality.  Native  children  constitute  the 
class  of  newcomers  most  accessible  for  making  the  estimate." 

The  most  accurate  method  of  determining  the  index  en- 
demicus  of  an  area  is  to  make  a  large  number  of  blood 
examinations  of  native  children  at  various  ages.  This  requires 
a  great  deal  of  time.  It  has  been  repeatedly  shown  that  in 
regions  where  malaria  prevails  extensively  a  large  per  cent, 
of  young  children  harbor  the  parasites  without  manifesting 
any  symptoms  of  the  disease,  the  index  decreasing  as  the 
age  increases.  For  this  reason  young  natives  with  latent 
malaria  are  the  source  of  the  greatest  danger  to  the  com- 
munity. 

Koch78  records  the  following  indices : 

At   Bogadjim  :  Per  Cent.  Infected. 

Children  under  two  years 80.0 

Children   from  two  to   five  years 41.6 

Persons  over  five  years 

At   BongU  :  Per  Cent.  Infected. 

Children  under  two  years 100.0 

Children  from  two  to  five  years 46.1 

Children  from  five  to  ten  years 23.5 

Persons  over  ten  years 

Panse's89  observations  at  Tanga  may  be  tabulated  thus : 

Per  Cent.  Infected. 

Children  under  one  year 48.0 

Children  from  one  to  three  years 87.6 

Children  from  four  to  seven  years 65.1 

Older  children  and  youths 39.4 

Adults    15-3 

Similar  results  were  noted  by  Schaudinn90  in  San  Michele 
di  Leme: 

1901.  Per  Cent.  Infected. 

Children  under  five  years 100.0 

Children  from  five  to  ten  years 83.0 

Children  from  ten  to  fifteen  years 100.0 

Persons  from  fifteen  to  sixty  years   

1902.  Per  Cent.  Infected. 

Children  under  five  years 100.0 

Children  from  five  to  ten  years 100.0 

Children  from  ten  to  fifteen  years 83.0 

Persons  from  fifteen  to  sixty  years 7-7 

Annett,  Dutton  and  Elliott,91'  in  Nigeria,  obtained  the  results 
recorded  in  the  following  tabulation : 


58  THE   STUDY   OF  MALARIA 

Age.  Per  Cent.  Infected. 

Under  one  year 27.3 

From  one  to  two  years 63.0 

From  two  to  three  years 63.0 

From  three  to  four  years 51.0 

From  four  to  five  years 48.8 

From  five  to  six  years 38.8 

From  six  to  seven  years 6.6 

From  seven  to  eight  years 27.5 

From  eight  to  nine  years 25.0 

From  nine  to  ten  years 14.0 

Ten  years  and  over 10.0 

Craig91  reports  the  endemic  index  about  Camp  Stotsenburg 
as  follows: 

Per  Cent. 

From  one  to  five  years 72.5 

From  five  to  ten  years 37.0 

From  ten  to  fifteen  years 24.5 

In  calculating-  the  endemic  index  a  sufficiently  large  number 
of  persons  should  be  examined  in  order  to  eliminate  error. 
It  has  been  estimated  that  if  fifty  persons  be  examined  and  the 
blood  of  twenty-five  found  to  contain  parasites,  the  margin 
of  error  being  20  per  cent.,  the  index  would  not  be  50  per 
cent.,  but  between  30  and  70  per  cent.  Furthermore,  while  a 
high  index  indicates  widespread  malaria,  an  index  of  zero 
must  not  be  construed  to  indicate  an  entire  absence  of  the 
disease,  since  experience  has  shown  that  it  may  exist  where 
the  index,  estimated  in  this  manner,  is  zero. 

In  comparing  the  indices  of  two  localities  the  figures  should 
be  taken  at  corresponding  seasons,  since  the  index  of  a  given 
locality  varies  according  to  season.  Thus  Rogers4*  observed 
in  the  tea  gardens  of  Assam  that  the  endemic  index  reached 
80  per  cent,  in  October,  but  was  only  30  per  cent,  in  the  same 
place  early  in  April.  Laveran1  states  that,  while  the  endemic 
index  of  a  certain  portion  of  Java  was  57.5  per  cent,  in  Janu- 
ary, it  fell  to  32  per  cent,  in  May. 

The  prevalence  of  splenic  enlargement  has  been  employed 
to  calculate  the  extent  of  paludism,  this  method  requiring 
much  less  time  than  the  examination  of  the  blood.  Among 
unhealthy  villages  of  Borneo,  Nieuwenhuis86  found  the  spleen 
enlarged  in  80  per  cent,  of  the  children  examined.  Schellong92 
found  the  spleen  index  at  Finschhafen  to  be  84  per  cent.    An 


ETIOLOGY  59 

examination  of  the  school  children  held  at  Marathon  in  Octo- 
ber, 1906,  showed  that  enlargement  of  the  spleen  was  to  be 
found  in  every  pupil.93 

The  spleen  rate  and  the  endemic  index,  estimated  by  a  micro- 
scopic examination  of  the  blood,  do  not  usually  correspond 
even  approximately.  In  Algeria  the  Sergents88  found  the 
spleen  rate  in  children  from  one  to  five  years  old  to  be  63.58 
per  cent.,  while  the  parasite  rate  was  only  18.18  per  cent. 
Stephens  and  Christophers94  have  prepared  the  following  table 
to  illustrate  the  relation  between  the  spleen  rate  and  the 
parasite  rate : 

Locality.  Spleen  Rate.        Endemic  Index. 

Calcutta   0.0  0.0 

Jalpaiguri — 

Bustee  children 27.0  16.1 

School  children 14.7  0.0 

Babu    children 14.2  0.0 

Mainaguri    74.0  25.0 

Rungamutty    83.0  43.6 

Sam    Sing 7.1  16.0 

Kurseong    1 0.0  0.0 

Kurseong  II 0.2  0.0 

These  investigators  draw  the  following  conclusions : 

1.  A  high  endemic  index  may  exist  without  any  appreciable 
spleen  rate  (Africa). 

2.  A  high  spleen  rate  may  exist  in  adults  without  a  corre- 
sponding parasite  infection. 

3.  In  India  (Bengal)  among  children  a  high  spleen  rate  is 
a  fair  indication  of  the  parasite  infection. 

4.  The  spleen  rate,  unlike  the  parasite  rate,  increases  up 
to  a  certain  age  limit  and  may  be  considerable  when  the  para- 
site rate  is  nil. 

The  writer  does  not  believe  that  the  spleen  rate  would  dis- 
close the  true  endemic  index  of  regions  in  the  Southern  States. 

Length  of  Residence. — In  highly  malarial  regions,  espe- 
cially in  the  tropics,  newcomers  are  usually  infected  during  the 
first  year.  Craig70  says  that  of  the  hundreds  of  cases  of 
malaria  occurring  in  our  soldiers  in  Cuba  almost  95  per  cent, 
gave  a  history  of  being  there  from  two  to  six  weeks  before 
the  onset  of  the  disease,  and  that  one  month  was  the  period 
most  commonly  given. 


60  THE   STUDY   OF   MALARIA 

In  the  Southern  States  the  period  before  infection  varies 
greatly  according  to  circumstances.  Newcomers  who  live  in 
hygienic  surroundings,  and  who  observe  ordinary  precautions, 
may  go  for  years  without  developing  the  disease.  On  the  other 
hand,  persons  coming  South  who  take  no  precautions,  and 
who  expose  themselves  carelessly,  are  liable  to  be  attacked 
early.  Thus,  it  is  said  that  when  the  Beaumont  oil  fields  were 
opened  up  people  flocked  there  from  nearly  every  section  of 
the  country,  and  nearly  every  newcomer  was  struck  down 
within  a  few  weeks  with  malarial  fever  in  some  form. 

Residence,  even  prolonged,  in  a  malarial  locality  does  not 
confer  absolute  immunity  to  malaria.    . 

Change  of  Residence. — The  effect  of  a  change  of  residence 
upon  the  immunity  in  the  negro  race  has  been  referred  to. 

It  is  a  common  observation  that  moving  to  another  locality 
"brings  the  malaria  out  of  the  system."  This  malaria  is 
usually  latent — always  so,  of  course,  if  the  new  residence  is 
in  a  non-malarial  region.  It  is  not  uncommon  for  persons 
who  have  never  had  recognizable  paroxysms  to  suffer  an  out- 
break upon  leaving  the  endemic  region. 

Occupation. — This  is  a  factor  in  the  etiology  of  malaria 
in  two  respects :  first,  by  reason  of  certain  occupations  exposing 
the  person  to  the  bites  of  mosquitoes;  second,  by  reason  of 
the  exposure  and  exertion  attending  certain  occupations  awak- 
ening latent  malaria. 

Rural  avocations  more  commonly  expose  to  malaria  than 
urban.  Occupations  which  necessitate  residence  at  highly 
malarious  spots  are  especially  dangerous,  as  well  as  those  that 
require  being  out  of  doors  at  night. 

Overturning  the  soil,  as  in  gardening,  farming,  ditching, 
railroad,  levee,  and  canal  construction,  predisposes  to  malarial 
infection.  Fishermen,  soldiers,  night-watchmen,  engineers, 
and  timber-workers  are  often  exposed. 

Rice  culture,  requiring  as  it  does  the  retention  of  water 
from  the  surface  of  the  ground,  is  not  an  unalloyed  boon  as 
an  innovation  into  many  of  our  Southern  States.  The  dangers 
to  the  community  from  the  growth  of  rice  were  recognized 
many  decades  ago  near  Savannah  and  Charleston.     Malaria 


Fig.   7. — Exposure  to  the  sun  is  one  of  the  predisposing  causes  of  malaria. 


ETIOLOGY  6 1 

is  said  to  have  almost  disappeared  from  the  regions  of  Parma 
and  Vincenza  when  rice  culture  was  discontinued. 

Social  Condition.  Civilization. — Formerly  malaria  at- 
tacked all  classes.  Many  noted  persons  were  frequently  in- 
fected, and  James  I  and  Cromwell  died  of  the  disease.  Moats 
and  lakes  near  castles  and  country  estates  were  doubtless  to 
blame. 

Now  malaria  is  chiefly  a  disease  of  the  poor  and  ignorant 
classes.  The  man  in  the  well-constructed  and  properly- 
screened  residence  is  much  less  liable  to  become  infected  than 
the  one  in  the  loosely  built  and  unprotected  hut.  The  occupa- 
tions and  food  of  the  poorer  classes  are  also  factors  in  the 
greater  prevalence  among  them. 

Persons  living  in  cities  and  towns  are  much  less  apt  to  be 
exposed  to  infection  than  those  in  villages  and  in  the  country. 
Many  towns  and  cities  in  the  heart  of  malarial  areas  are  rela- 
tively free  from  the  disease.  Suburbs  are  more  highly  mala- 
rious than  the  more  dense  populated  sections,  for  the  reason 
that  the  mosquito  has  more  opportunity  to  breed  in  the  former. 

Other  Factors. — There  are  certain  factors  of  the  utmost 
importance  in  the  etiology  of  malaria,  and  before  the  truth 
was  known  were  looked  upon  as  causing  the  disease.  These 
are  overwork,  fatigue,  exposure  to  sun,  rain,  and  cold,  excesses 
in  Bacchus  and  in  Venus,  psychic  emotions,  loss  of  sleep,  trau- 
matism, surgical  intervention,  overeating,  hunger,  thirst,  diges- 
tive disorders,  menstruation,  parturition,  intercurrent  affec- 
tions, and  the  administration  of  certain  medicaments. 

Watermelons,  muscadines,  cucumbers,  and  other  articles 
have  yet  the  reputation  in  parts  of  the  South  of  causing  chills. 

The  administration  of  tuberculin  and  of  potassium  iodide 
are  said  to  be  followed  not  infrequently  by  outbursts  of 
malaria. 

It  is  obvious  that  the  influence  of  these  factors  is  upon  latent 
malaria,  or  the  parthenogenetic  cycle  of  the  parasite's  life  his- 
tory. 

Insufficient  and  improper  food  both  lowers  the  resistance 
to  new  infections  and  kindles  latent  malaria  into  activity. 


62  THE   STUDY   OF   MALARIA 

The  effect  of  deficient  nourishment  upon  malaria  mortality 
is  well  illustrated  by  the  following  table,  compiled  by  Roux 
from  statistics  in  India,  where  rice  is  the  staple  food  of  the 
lower  classes : 

Year.  Price  of  Rice.  Deaths  from  Malaria. 

1874 2  rupees  4  891 

1875 2  rupees  9  842 

1876 2  rupees  12  902 

1877 3  rupees  12  991 

1878 4  rupees  8  1,002 

While  the  major  portion  of  many  older  works  on  malaria 
was  devoted  to  the  role  of  drinking  water  in  the  contagion  of 
malaria,  it  is  now  known  that  it  is  of  minor  importance. 

Celli67  had  several  healthy  individuals,  in  the  San  Spirito 
Hospital  of  Rome,  to  drink  for  a  number  of  days  water 
obtained  from  the  Pontine  marshes  and  from  stagnant  pools. 
The  results  were  uniformly  negative. 

Zeri67  conducted  three  series  of  experiments  with  water 
from  malarious  localities:  1.  He  had  nine  individuals  drink 
from  iy2  to  3  litres  of  water  daily  from  five  to  twenty  days, 
each  person  consuming  from  10  to  60  litres  of  the  water.  2.  In 
sixteen  individuals  the  mucous  membranes  of  the  respiratory 
tract  were  sprayed  with  marsh  water  by  means  of  a  com- 
pressed-air atomizer.  3.  In  five  persons  water  from  malarial 
places  was  injected  into  the  rectum.  The  results  of  all  these 
experiments  were  negative. 

It  has  been  maintained  that  water  in  which  mosquitoes  har- 
boring parasites  have  died  is  capable  of  producing  malaria. 
This  is  based  upon  the  single  experiment  of  Ross,  who  had 
an  Indian  native  drink  a  small  quantity  of  water  in  which 
there  were  dead  mosquitoes  which  had  fed  upon  malarial 
blood.  Eleven  days  later  the  native  developed  fever  which 
terminated  spontaneously  after  three  days  without  relapsing. 
In  the  blood  were  found  ring  forms  of  the  estivo-autumnal 
parasite.  This  experiment  was  repeated,  but  the  result  could 
not  be  confirmed,  so  must  be  regarded  as  co-incidental. 

In  regard  to  the  immunity  to  malaria  enjoyed  by  opium- 
eaters,  Russell95  states  that  the  observations  of  several  sur- 


ETIOLOGY  63 

geons  of  extensive  experience  in  opium-eating  regions  confirm 
the  popular  belief  that  the  opium-eater,  in  the  early  stages  of 
the  habit,  while  as  yet  not  constitutionally  broken  by  its  long 
continuance,  does,  as  a  matter  of  fact,  enjoy  considerable 
immunity  from  malarial  affections.  This  writer  concludes  that 
this  power  of  opium  is  partially  responsible  for  its  prevalence 
in  some  of  the  eastern  countries.  Moore15  testifies  also  that 
opium-smokers  are  more  resistant  to  malaria. 

Epidemics. — Malaria,  known  as  an  endemic  disease,  occa- 
sionally prevails  so  intensely  as  to  acquire  the  dignity  of  an 
epidemic.  Becoming  more  frequent  and  fatal  in  its  native 
haunts,  it  may  spread  to  regions  ordinarily  immune,  and  may 
even  assume  the  extent  of  a  pandemic. 

The  first  pandemic  of  which  we  have  any  knowledge  oc- 
curred in  1557  to  1558,  and  is  said  to  have  overspread  all 
of  Europe.  The  next  appeared  from  1678  to  1682,  and  was 
nearly  as  extensive  as  the  former.  Similar  epidemics  arose 
during  1718-1722,  1 748-1 750,  1770- 1772,  and  1 779-1 783. 
During  the  past  century  an  epidemic  occurred  from  1806  to 
1812,  and  one  from  1823  to  1827  is  said  by  Hirsch18  to  have 
been  one  of  the  most  extensive,  severe,  and  persistent  of  pan- 
demics, of  which  reports  were  received  from  almost  all  parts 
of  the  world.  Between  1845  and  1849  an^  1855  and  i860 
malaria  assumed  epidemic  form,  and  the  great  pandemic  of 
1866  to  1872  marked  the  invasion  of  Mauritius  and  Reunion, 
where  malaria  was  previously  unknown. 

Quite  recently  epidemics  of  malaria  have  been  reported  in 
Algiers,  Greece,  and  elsewhere. 

What  may  be  called  house  epidemics  or  domestic  epidemics 
are  common  in  the  experience  of  many  observers. 

It  is  well  known  that  the  residents  of  certain  houses  suffer 
much  from  malaria,  and  that  certain  houses  are  seldom  free 
from  the  disease  during  the  malarial  season.  For  this  local 
conditions  are  responsible. 

The  writer  has  more  than  once  seen  as  many  as  half  a 
dozen  cases  in  one  family  at  the  same  time,  and  in  many  fami- 
lies every  member  is  successively  attacked  during  the  season. 

Modes  of  Infection. — The  only  known  modes  of  transmis- 


6j\.  the  study  of  malaria 

sion  of  malaria  necessary  to  consider  are:  i,  congenital;  2, 
artificial  inoculation,  and  3,  inoculation  through  the  bites  of 
certain  species  of  mosquitoes. 

Congenital  Malaria. — It  was  formerly  believed  that  malaria 
was  not  infrequently  transferred  from  mother  to  fetus. 
Ducheck96  published  a  case,  in  1858,  of  a  child  whose  mother 
suffered  from  malarial  paroxysms  during  pregnancy.  The 
child  dying  three  hours  after  birth,  at  autopsy  the  liver  and 
spleen  were  found  to  be  enlarged,  and  the  spleen  and  blood 
of  the  portal  vein  contained  considerable  pigment. 

Two  cases  are  reported  by  Felkin.97  In  the  first  case  the 
diagnosis  was  based  upon  intrauterine  quivering  of  the  fetus, 
enlarged  spleen  at  birth,  and  fever  later,  the  date  of  which  is 
not  recorded.  In  the  second  case  the  mother  had  never  had 
malaria,  having  never  been  outside  of  Edinburgh,  but  the 
infection  is  attributed  to  the  father,  who  had  contracted  mala- 
ria in  Africa  several  years  previously  and,  as  Felkin  believes, 
had  transmitted  the  disease  to  no  less  than  three  infants. 

Watson72  cites  the  case  of  a  woman  who  was  suffering  with 
tertian  ague.  On  alternate  days  when  she  missed  the  parox- 
ysms she  could  feel  the  child  shiver  with  chills.  Bark  was 
prescribed  and  the  paroxysms  of  the  fetus  were  first  inter- 
rupted, then  those  of  the  mother. 

However,  of  numerous  cases  recorded  by  a  score  or  more 
of  early  writers,  all  are  open  to  two  objections:  First,  the 
diagnosis  was  not  certainly  established;  secondly,  postnatal 
infection  was  not  excluded. 

Marchiafava  and  Bignami22  mention  four  cases  in  which 
the  blood  of  the  fetuses  of  malarial  mothers  was  entirely 
negative. 

Thayer98  records  a  case  of  a  negress  who  had  had  malaria 
at  least  five  months  and  whose  blood  contained  three  groups 
of  the  quartan  parasites  when  she  gave  birth,  during  a 
paroxysm,  to  a  child  whose  blood,  upon  repeated  examination, 
was  found  free  from  parasites  and  pigment.  While  both  para- 
sites and  pigment  were  found  upon  the  maternal  side  of  the 
placenta,  none  was  found  upon  the  fetal  side. 

Sereni,86  who  examined  the  blood  of  four  infants  born  of 


ETIOLOGY  65 

malarial  mothers,  was  unable  to  find  evidences  of  malaria  in 
any  case. 

Ziemann,48  likewise,  in  four  cases  of  new-born  children  of 
malarial  infected  mothers,  had  uniformly  negative  results. 

The  writer  has  upon  several  occasions  obtained  blood  from 
infants,  immediately  after  birth,  whose  mothers  harbored 
malarial  parasites,  and  in  no  case  have  parasites  been  detected. 
Similar  results  have  been  obtained  by  Bastianelli,22  Caccini,22 
Borne,90  Schoo,90  F.  Plehn,5  Terburgh,79  A.  Plehn,"  Wellman,68 
and  others. 

Pezopoulos  and  Cardamatis100  based  the  following  conclu- 
sions upon  six  cases,  five  full-term  labors  and  one  abortion, 
which  they  studied. 

1.  In  the  blood  of  the  six  mothers  there  were  parasites, 
more  or  less  abundant. 

2.  In  the  blood  of  the  new-born  and  of  the  aborted  foetus, 
examined  a  few  hours  after  expulsion,  there  were  no  parasites. 

3.  In  the  blood  of  the  liver  and  spleen,  as  well  as  in  sections 
of  these  organs  of  the  two  fetuses  which  were  examined 
postmortem,  no  parasites  were  found. 

4.  In  the  blood  taken  from  the  maternal  surface  of  the 
placentae  of  the  five  new-born  children  there  were  parasites  in 
abundance,  while  in  the  blood  taken  from  the  fetal  surface 
there  were  no  parasites,  or  at  most  a  very  few. 

5.  In  blood  taken  from  the  umbilical  cord  no  parasites  were 
found. 

6.  In  the  blood  of  the  placenta  of  the  aborted  fetus  no 
parasites  could  be  detected. 

Bein  and  Kohlstock101  are  said  to  have  found  malarial  para- 
sites in  the  blood  of  a  four-months-old  child  born  sometime 
after  the  arrival  of  the  mother  in  a  region  free  from  malaria. 

Winslow102  records  a  case  which  he  believes  to  be  congenital, 
though  the  parasites  were  not  detected  until  the  child  was 
eleven  weeks  old. 

A  case  of  malarial  fever  in  infancy  thought  to  be  maternal 
in  origin  is  reported  by  Peters.103     The  examination  of  the 
blood  on  the  second  and  third  days  after  birth  was  negative, 
though  parasites  were  found  on  the  fifty-first  day. 
5 


66  THE   STUDY  OF  MALARIA 

Moffatt104  observed  a  case  supposed  to  be  congenital  malaria, 
though  the  parasites  were  not  detected  before  the  seventh 
week. 

Bouzian,M5  in  Algeria,  detected  parasites  in  the  blood  of  an 
infant  only  twelve  days  old. 

Hitte106  collected  from  the  literature  21  cases  of  malaria 
considered  congenital.  In  13  of  these  the  blood  was  not 
examined;  in  1  parasites  were  detected  four  months  after 
birth,  and  in  5  cases  parasites  were  found  from  several  weeks 
to  two  months  after  birth.  The  remaining  2  cases  were  ob- 
served by  Hitte  personally,  who  claims  to  have  found  parasites 
in  the  blood  obtained  from  the  umbilical  cords.  The  mothers 
of  both  children  were  suffering  with  malaria. 

Parasites  were  found  by  Simms  and  Warwick85  in  the  blood 
of  three  babies  between  three  and  seven  days  old ;  the  mothers 
had  previously  had  malarial  paroxysms. 

Holt107  mentions  a  case  in  which  he  states  there  seems  little 
doubt  that  the  disease  was  contracted  in  utero.  The  mother 
had  been  suffering  with  tertian  intermittent.  Eighteen  hours 
after  birth  the  child  showed  evidences  of  a  malarial  paroxysm. 
The  next  day  malarial  organisms  were  found  in  the  blood. 

Economous108  reports  6  cases  with  almost  conclusive  evi- 
dence of  congenital  origin.  In  each  of  these  cases  the  blood, 
examined  from  eight  to  forty-eight  hours  after  birth,  con- 
tained malarial  parasites.  The  mothers  had,  previous  to  deliv- 
ery, suffered  with  malaria. 

Bel109  mentions  a  female  patient  who  died  of  pernicious 
malaria.  The  parasite  was  found  in  the  blood,  pericardium, 
meninges,  and  spleen,  as  well  as  in  a  seven-months  fetus. 

As  may  be  inferred,  properly  proven  cases  of  congenital 
malaria  are  rare.  This  reluctance  of  the  parasites  to  pass 
through  the  placenta  is  in  keeping  with  their  aversion  to  leave 
the  blood-vessels.  It  has  been  pointed  out  that  no  parasites 
are  found  in  the  hemorrhages  and  perivascular  exudates  in 
cases  of  pernicious  malaria,  though  they  may  exist  in  hordes 
within  the  vessels.  .  Congenital  malaria  is  probably  to  be  ex- 
plained in  the  majority  of  cases  through  placental  lesions 
permitting  direct  mingling  of  maternal  and  fetal  blood  during 
parturition. 


ETIOLOGY 


67 


Inoculation. — Even  before  the  parasite  of  malaria  was  dis- 
covered Gerhardt110  succeeded,  employing  the  blood  of  mala- 
rial subjects,  in  inoculating  healthy  persons  with  malaria. 

Since  then  many  similar  experiments  have  been  performed. 
Tertian  malaria  has  been  transmitted  by  inoculation  by  Bein, 
Bacelli,  Antolisei  and  Angelini,  Mannaberg,  Elting,  and  others ; 
quartan  by  Gualdi  and  Antolisei,  Di  Mattei,  Calandruccio, 
Bacelli,  and  Celli  and  Santori ;  estivo-autumnal  by  Gualdi  and 
Antolisei,  Di  Mattei,  Celli  and  Santori,  Bastianelli  and  Big- 
nami,  and  Elting. 

The  injection  of  blood  containing  only  crescents  gave  nega- 
tive results  in  the  experiments  of  Thayer,  Bastianelli,  Big- 
nami,  and  Elting.  Di  Mattei  and  Calandruccio,  however, 
observed  an  irregular  form  of  fever  to  follow  such  an  injec- 
tion.    This  can  be  explained  only  by  parthenogenesis. 

The  injection  of  blood  containing  a  certain  species  of  para- 
sites is  followed  by  fever  characteristic  of  that  species,  and 
these  parasites  are  to  be  found  in  the  blood  of  the  person 
inoculated. 

There  are  only  two  experiments  which,  at  first  sight,  seem 
to  contradict  this  specificity  of  the  different  parasites.  These 
were  performed  by  Gualdi  and  Antolisei.  Blood  from  two 
patients  suffering  with  quartan  malaria  was  inoculated  into 
two  healthy  persons.  In  one  case  the  injection  was  followed 
in  ten  days  by  irregular  fever  and  estivo-autumnal  parasites 
were  detected  in  the  blood.  In  the  other  case  after  twelve 
days  an  irregular  fever  began  and  estivo-autumnal  and  a  few 
quartan  parasites  were  found  in  the  blood.  It  was  later  dis- 
covered that  the  patients  from  whom  the  blood  was  taken 
had  recently  suffered  with  quotidian,  tertian,  quartan,  and 
irregular  fever,  hence  it  is  evident  that  a  pure  culture  of 
quartan  parasites  was  not  obtained.  These  same  observers,  in 
subsequent  experiments,  found  that  the  injection  of  one  species 
of  parasite  was  followed  by  the  characteristic  fever  and  the 
appearance  of  the  same  species  of  parasites  in  the  blood  of 
the  person  inoculated. 

There  are  those  who  cannot  be  successfully  inoculated  with 
one  species  of  parasite  but  can  with  another.     It  has  been 


68  THE   STUDY  OF  MALARIA 

shown  also  that  one  species  of  parasite  often  disappears  from 
the  blood  upon  inoculation  with  a  different  species.  Di  Mattei 
found  that  the  inoculation  with  estivo-autumnal  parasites  of  a 
patient  already  infected  with  quartan  malaria  caused  a  disap- 
pearance of  the  quartan  and  a  development  of  the  estivo- 
autumnal  parasites,  and  that  the  inoculation  with  quartan 
parasites  of  a  patient  already  infected  with  estivo-autumnal 
caused  a  disappearance  of  the  latter  and  a  de\-elopment  of 
the  quartan  parasites. 

The  degree  of  development  of  the  parasites  apparently  has 
no  effect  upon  the  result,  since  the  disease  develops  as  readily 
after  the  injection  of  blood  containing  adult  organisms  as 
after  that  containing  young  parasites.  It  is  immaterial  also 
whether  the  blood  be  injected  intravenously  or  subcutaneously. 
A  very  small  amount  of  blood,  even  less  than  one  drop,  is 
often  sufficient  for  inoculation. 

The  injection  of  defibrinated  blood,  of  centrifugalized  cor- 
puscles, and  of  blood  diluted  with  an  equal  quantity  of  dis- 
tilled water  and  inoculated  immediately  have  given  positive 
results.  The  injection  of  dissolved  dried  blood,  and  blood 
diluted  with  an  equal  quantity  of  distilled  water  and  allowed 
to  stand  an  hour,  have  proven  negative. 

Jeffries111  reports  the  case  of  a  New  York  surgeon  who  had 
never  had  malaria  supposed  to  have  contracted  the  disease  by 
pricking  his  finger  several  times  during  an  operation  upon  a 
woman  infected  with  malaria.  Sixteen  days  after  the  opera- 
tion the  surgeon  had  the  first  chill  and  had  several  subse- 
quently. The  blood  contained  many  estivo-autumnal  para- 
sites. 

Dochmann86  attempted  to  inoculate  malaria  from  man  to 
man  by  means  of  the  serum  from  a  herpetic  vesicle.  While 
he  claims  to  have  succeeded,  the  results  of  his  experiments 
have  never  been  confirmed. 

Efforts  to  inoculate  the  lower  animals  with  human  malaria 
have  been  fruitless.  Such  attempts  have  been  made  upon 
horses,  mules,  dogs,  monkeys,  rabbits,  mice,  guinea-pigs, 
hedge-hogs,  bats,  wolves,  cats,  pigeons,  doves,  magpies, 
screech-owls,  turtles,  frogs,  and  lizards. 


ETIOLOGY  69 

DISSEMINATION  OF  MALARIA  BY  MOSQUITOES 
The  discovery  by  Ross  of  the  role  of  the  mosquito  in  the 
dissemination  of  malaria  is  the  most  startling  achievement  of 
modern  medical  science. 

Mosquitoes  do  not  cause  malaria;  they  carry  it  from  in- 
fected to  healthy  persons.  The  parasites,  sucked  with  blood 
from  a  malarial  individual,  undergo  a  cycle  of  development 
within  the  body  of  the  mosquito,  and  are  then  inoculated  into 
healthy  persons.  Man  is  merely  the  intermediate  host  of  the 
parasite,  the  mosquito  is  the  definitive  host,  and  it  has  been 
said  that  man  gives  malaria  to  the  mosquito,  and  not  the 
mosquito  to  man. 

Not  all  species  of  mosquitoes  can  serve  as  hosts  for  the 
malarial  parasite.  It  is  only  certain  members  of  the  sub- 
family Anophelince  that  have  been  found  to  act  in  this  capa- 
city. Of  this  subfamily  the  following  have  been  determined, 
with  more  or  less  certainty,  to  be  malaria  carriers: 


Anopheles  annulipes. 
Anopheles  bifurcatus. 
Anopheles  cohacsus. 
Anopheles  crucians. 
Anopheles  farauti. 
Anopheles  fluvialis. 
Anopheles  formoscensis. 
Anopheles  maculipennis. 
Anopheles  martini. 
Anopheles  punctipennis. 
Anopheles  pursati. 
Anopheles  vagus. 
Anopheles  vincenti. 
Cellia  albipes. 
Cellia  argyrotarsus. 
Cellia  pharcensis. 
Myzomyia  Christophersi. 
Myzomyia  culicifacics. 
Myzomyia  fnnesta. 
Myzomyia  Hispaniola. 
Myzomyia  Listoni. 


Myzomyia  Ludlozvii. 
Myzomyia  Lutzii. 
Myzomyia  picta. 
Myzomyia  Rossii. 
Myzomyia  Turkhudi. 
Myzorhynchus  barbirostris. 
Myzorhynchus  Coustani. 
Myzorhynchus  paludis. 
Myzorhynchus  sinensis. 
Myzorhynchus  Ziemanni. 
Nyssorhynchus  fidiginosus. 
Nyssorhynchus  Jamesii. 
Nyssorhynchus  macidatus. 
Nyssorhynchus  macidipalpis. 
Nyssorhynchus  Stephcnsii. 
Nyssorhynchus  Theobaldi. 
Pyretophorus  Chaudoyei. 
Pyrctophorus  costalis. 
Pyretophorus  jcypurensis. 
Pyretophorus  superpictus. 


70  THE    STUDY   OF    MALARIA 

Not  all  of  these  mosquitoes  serve  equally  well  as  hosts  of 
the  malarial  parasites.  Myzomyia  Rossii  is  a  very  poor  car- 
rier of  malaria,  while  the  Christophersi  is  a  very  efficient  car- 
rier. 

As  yet  very  little  is  known  of  the  relation  between  the 
species  of  mosquitoes  and  species  of  malarial  parasites.  Pyre- 
tophorns  costalis  is  known  to  transmit  tertian,  quartan,  and 
estivo-autumnal  malaria,  while  Myzorhynchus  sinensis  carries 
tertian  and  quartan,  but  not  estivo-autumnal  malaria. 

It  is  possible  that  some  mosquitoes  acquire  a  sort  of  im- 
munity to  malaria  which  may  account  for  their  incompetence 
as  malaria  disseminators.  There  are  certain  regions  where, 
in  spite  of  members  of  a  malaria-bearing  species  of  mosquito 
and  the  immigration  of  infected  persons,  malaria  does  not 
spread,  though  temperature  and  other  conditions  are  appar- 
ently favorable. 

The  food  of  mosquitoes  has  much  to  do  with  their  suscepti- 
bility to  infection.  Experiments  have  shown  that  Anopheles 
macnlipennis  fed  upon  fruits  and  sweets  are  not  readily  in- 
fected from  feeding  upon  malarial  blood,  but  if  allowed  only 
water  for  several  days  before  and  after  feeding  on  malarial 
blood  they  are  almost  always  infected. 

One  feeding  upon  blood  containing  parasites  does  not  always 
suffice  to  infect  the  mosquito.  Daniels,112  investigating  this 
subject,  examined  fifty-seven  mosquitoes  which  had  fed  once 
or  oftener  at  intervals  of  two  days. 

Per  Cent. 

Nineteen  fed  only  once,  and  five  had  zygotes 26.0 

Thirteen  fed  twice,  and  six  had  zygotes 46.0 

Sixteen  fed  three  times,  and  ten  had  zygotes 62.0 

Nine  fed  four  times,  and  six  had  zygotes 66.6 

Of  these  57  anopheles  27,  or  47.5  per  cent.,  were  infected. 

The  effect  of  fertilization  upon  the  power  of  mosquitoes  to 
transmit  malaria  is  not  definitely  settled,  but  it  is  thought  by 
some  that  fertilized  females  are  the  most  desirable,  if  not 
indeed  the  sole,  hosts  of  the  parasite. 

In  order  that  anopheline  mosquitoes  may  be  infected  from 
malarial  blood  it  is  necessary  that  the  sexual  forms  of  the 


ETIOLOGY  71 

parasite  be  present  in  sufficient  numbers,  of  proper  maturity, 
and  suitable  proportion  of  sexes. 

How  is  the  existence  of  the  malarial  parasite  perpetuated; 
why  does  not  the  disease  become  extinct  over  winter  when 
there  are  apparently  no  mosquitoes  to  further  the  life  history 
of  the  organism? 

The  subject  of  latent  or  chronic  malaria  furnishes  the  solu- 
tion. The  parasites  here  lie  dormant  or  undergo  partheno- 
genesis at  longer  or  shorter  intervals,  and  are  ready  the  fol- 
lowing season  for  the  sexual  cycle  in  the  body  of  the  definitive 
host,  the  mosquito. 

It  is  possible  that  in  a  few  instances  the  parasites  persist  in 
the  bodies  of  hibernating  mosquitoes.  While  some  investiga- 
tions have  led  to  a  different  conclusion,  Martirano  has  found 
in  the  neighborhood  of  Rome  as  late  as  the  middle  of  March 
that  from  1  to  5  per  cent,  of  anophelines  were  infected,  and 
Stephens  and  Christophers  observed  at  Freetown,  during  the 
dry  season  that  from  5  to  20  per  cent,  were  infected.90 

From  analogy  with  the  transference  of  Texas  fever  hema- 
tozoa  by  the  tick  to  its  progeny,  it  has  been  sought  to  establish 
such  an  inheritance  of  malarial  parasites  by  mosquitoes.  While 
Schaudinn  found  in  the  ovaries  of  an  anopheline  mosquito 
forms  which  he  considered  malarial  organisms,  no  other  inves- 
tigators have  been  able  to  confirm  this  observation,  and  it  must 
be  considered  as  yet  unproven  that  infected  mosquitoes  can 
communicate  the  infection  to  their  offspring.  It  was  also  be- 
lieved that  infected  mosquitoes  dying  in  the  water  after  ovi- 
position  and  being  eaten  by  larvae  might  thus  communicate 
the  parasites  to  these  larvae.  This  has,  however,  not  been 
determined. 

The  relation  of  the  mosquito  to  malaria  explains  the  preva- 
lence of  the  latter  with  reference  to  season,  temperature,  and 
rainfall.  It  explains  malaria  as  a  disease  chiefly  of  low  alti- 
tudes and  marshy  regions ;  a  disease  of  the  country  rather  than 
of  the  city.  House  epidemics  of  malaria  are  thus  rendered 
clear  and  the  relation  of  ship  malaria  and  proximity  to  the 
shore  becomes  obvious.  The  bearing  of  age,  sex,  and  occu- 
pation upon  the  endemic  is  in  thorough  harmony  with  the 


72  THE   STUDY   OF   MALARIA 

theory.  That  malaria  is  more  easily  contracted  at  night  is 
understood  from  the  feeding  habits  of  the  malarial  mosquitoes. 
That  all  measures  directed  toward  the  prevention  of  mosquito 
bites  are  followed  by  a  commensurate  reduction  of  the  preva- 
lence of  malaria  is  one  of  the  strongest  arguments.  The 
analogy  with  filiariasis,  Texas  fever,  hematozoan  infection  of 
birds,  and  similar  diseases  strengthens  the  theory.  Numerous 
and  accurate  experiments  have  absolutely  proven  the  dissemi- 
nation of  malaria  by  certain  mosquitoes.  One  of  the  earliest 
of  these  was  that  of  Dr.  Patrick  Manson.  Mosquitoes  fed  on 
tertian  malarial  blood  in  Rome  under  the  supervision  of  Bas- 
tianelli  were  sent  in  suitable  cages  to  London.  There  they 
were  permitted  to  bite  Dr.  Thurburn  Manson  and  Mr.  George 
Warren,  neither  of  whom  had  ever  been  previously  exposed 
to  malaria.  In  due  time  both  developed  malaria,  and  tertian 
parasites  were  found  in  the  blood  at  this  time  and  later  during 
several  relapses. 

The  sexual  cycle  of  the  parasite  within  the  mosquito  has 
been  followed  many  times. 

An  objection  that  has  been  frequently  urged  against  the 
"mosquito  theory"  is  that  there  are  numerous  localities  in 
which  mosquitoes  abound  and  from  which  malaria  is  entirely 
absent ;  indeed,  mosquitoes  are  said  to  be  well  nigh  intolerable 
in  portions  of  the  arctic  regions.  It  must  be  remembered, 
however,  that  only  a  certain  subfamily  of  mosquitoes  can 
serve  as  hosts  for  the  parasite.  Furthermore,  the  surrounding 
temperature  must  be  suitable  for  the  sexual  development  of 
the  parasites  within  the  definitive  host.  But  it  cannot  be  denied 
that  there  are  areas,  even  in  the  midst  of  a  malarial  country, 
in  which  anophelines  are  present,  the  temperature  is  favorable, 
and  other  conditions  apparently  suitable,  but  autochthonous 
malaria  does  not  appear.  Among  such  localities  reported  may 
be  mentioned  Singapore,  Penang,  Malacca,  Soekaboemie,  and 
portions  of  Brazil,  of  Italy,  and  of  Lower  Egypt.  This  has 
not  as  yet  been  satisfactorily  explained,  but  may  be  due  to  an 
acquired  immunity  on  the  part  of  the  mosquito,  or  to  the 
influence  of  their  food  on  the  development  of  the  parasite. 

It  was  formerly  maintained  that  there  were  highly  malarial 


ETIOLOGY  73 

regions  in  which  there  were  no  mosquitoes,  and  a  number  of 
such  places  have  been  reported.  But  in  each  case  where 
investigated  by  a  competent  observer  anopheline  mosquitoes 
have  been  found  where  malaria  is  endemic.  Koch69  mentions 
that  at  Tosari,  elevated  1,777  metres,  while  there  was  some 
malaria,  there  were  no  anopheles.  The  malaria  occurred, 
however,  in  those  who  were  employed  in  the  neighboring  low- 
lands and  not  in  the  children  who  remained  in  the  town. 

The  habits  of  the  anopheline  mosquitoes  are  such  that  they 
may  be  easily  overlooked  except  by  an  expert.  Retiring  to 
dark  recesses  during  the  day,  biting  only  at  night,  and  not 
singing  a  great  deal,  their  presence  may  not  be  felt,  especially 
by  persons  in  whom  the  bites  do  not  cause  much  irritation. 

It  may  therefore  be  stated  confidently  that  there  is  no 
endemic  malaria  without  mosquitoes. 

The  misproportion  between  the  number  of  infected  anophe- 
lines  and  the  number  of  cases  of  malaria  has  been  cited  to 
overthrow  the  mosquito  doctrine.  In  Algiers  Sergent90  found 
4  per  cent,  of  the  anopheles  and  100  per  cent,  of  the  children 
infected.  A.  Plehn79  found  in  one  of  the  most  malarial  locali- 
ties, Cameroon,  among  860  anopheles  only  2..2.  per  cent,  in- 
fected. Stephens  and  Christophers113  believe  that  about  5  per 
cent,  of  all  the  anopheles  of  tropic  Africa  are  infected.  At 
Aro  they  found  the  sporozoit  rate  in  anopheles  caught  in  native 
huts  to  be  50  per  cent. 

It  should  be  borne  in  mind  that  one  infected  anopheline 
mosquito  is  capable  of  infecting  a  number  of  persons.  Also 
the  sporozoit  rate  varies  according  to  season  and  according 
to  the  kind  of  mosquito,  since  it  has  been  shown  that  some 
species  are  better  malaria  carriers  than  others. 

The  fact  that  malaria  is  decreasing  in,  or  has  disappeared 
from,  regions  formerly  highly  malarial,  but  in  which  malaria- 
bearing  mosquitoes  are  yet  found,  is  another  argument  which 
has  been  proposed  against  the  relation  of  the  mosquito  to 
malaria.  With  reference  to  Great  Britain,  Nuttall,  Cobbett 
and  Strangeways-Pigg114  concluded  that : 

1.  The  disappearance  of  ague  from  Great  Britain  does  not 
depend  upon  the  extinction  of  mosquitoes  capable  of  harboring 
the  parasites  of  malaria. 


74  THE   STUDY   OF   MALARIA 

2.  Three  species  of  anopheles  (A.  maculipennis,  A.  bifur- 
catus,  A.  nigripes)  are  to  be  found  in  Great  Britain  in  all 
districts  which  were  formerly  malarious,  but  also  in  places 
concerning  which  there  is  no  record  of  the  former  prevalence 
of  ague. 

3.  The  anopheles  to-day  are  most  numerous  in  low-lying 
land  containing  many  ditches,  ponds,  and  slowly-flowing  water, 
suitable  for  their  habitat,  and  corresponding  to  the  districts 
where  ague  was  formerly  prevalent. 

4.  Since  the  disappearance  of  ague  does  not  depend  upon 
the  extinction  of  anopheles,  it  is  probably  due  to  several  causes 
operating  together : 

(a)  A  reduction  in  the  number  of  these  insects  consequent 
upon  drainage  of  the  land;  this  being  in  accord  with  all  the 
older  authors,  who  attributed  the  disappearance  of  ague  largely 
to  this  cause. 

(b)  Reduction  of  the  population  in  infected  districts  as  the 
result  of  emigration  about  the  time  when  ague  disappeared 
from  England.  This  would  naturally  reduce  the  number  of 
infected  individuals  and  thus  lessen  the  chance  of  the  anopheles 
becoming  infected. 

(c)  It  is  possible  that  the  use  of  quinine  has  reduced  the 
chances  of  infecting  the  anopheles  through  checking  the  devel- 
opment of  the  parasites  in  the  blood  of  subjects  affected  with 
ague. 

Finally,  it  has  been  maintained  that  persons  who  have  never 
had  malaria  have  contracted  it  in  uninhabited  wildernesses, 
where,  obviously,  only  uninfected  anophelines  would  be  found, 
since  man  is  the  only  intermediate  host  of  the  parasite. 

To  this  it  may  be  answered  that  no  such  instance  has  been 
so  accurately  reported  as  to  prove  conclusively  that  infection 
has  ever  occurred  under  these  circumstances. 

THE  MALARIA-BEARING  MOSQUITOES 

The  genus  Anopheles  was  established  in  18 18  by  Johann 
Meigen.  The  bestowal  of  the  name  appears  prescient,  since 
anopheles  signifies  troublesome  or  hurtful. 

Of  the  fifty  or  more  species  and  subspecies  of  anophelines 


ETIOLOGY  75 

now  known  seven  occur  in  the  United  States :  A.  maculipennis, 
A.  punctipennis,  A.  crucians,  A.  franciscanus ,  A.  barberi,  C. 
argyrotarsus,  and  C.  albipes. 

Breeding  Places. — The  different  species  of  anophelines  vary 
a  great  deal  in  the  choice  of  a  breeding  place.  Furthermore, 
with  each  species  there  may  be  said  to  be  places  of  choice  and 
places  of  necessity. 

Contrary  to  the  usual  custom  of  culex,  the  anopheles  usually 
selects  water  more  or  less  pure  in  which  to  deposit  her  ova. 
Ground  water  appearing  at  the  surface  is  especially  suitable. 
Pools  of  at  least  some  degree  of  permanence  are  preferred 
to  those  which  might  dry  before  the  aquatic  stage  of  the 
insect  is  completed.  Natural  accumulations  of  water  more 
often  contain  anopheles  larvae  than  do  artificial  collections. 
Pools,  ponds,  swamps,  inlets  of  lakes,  and  of  small,  slowly- 
flowing  streams,  ditches  along  roadsides,  canals,  borrow  pits 
along  railroads  and  levees,  and  rice  fields  are  common  breed- 
ing places.  Water  contained  in  the  tracks  of  animals  may 
harbor  larvae. 

When  water  is  scarce,  as  during  the  dry  season,  anopheline 
larvae  may  be  found  in  tubs,  barrels,  boats,  buckets,  bottles, 
cisterns,  mollusc  and  cocoanut  shells;  in  water  retained  by 
the  leaves  and  stalks  of  tropic  plants,  or  even  within  vases  in 
dwellings,  though  these  locations  are  to  be  regarded  as  places 
of  necessity  and  not  of  choice. 

While,  as  said,  clean  water  is  usually  chosen  by  these  mos- 
quitoes, at  least  one  species,  M.  Rossii,  is  known  to  breed  in 
very  foul  pools.  Another  species,  M.  Listoni,  is  said  to  breed 
in  swiftly-flowing  streams,  which  is  contrary  to  the  usual  habit 
of  this  subfamily. 

In  regard  to  salt  water  as  a  medium  for  anopheline  larvae 
many  opinions  are  held.  It  seems  that  the  species  indigenous 
to  the  United  States  do  not  breed  in  salt  water,  and  this  was 
the  experience  of  Celli  and  other  Italian  investigators.  How- 
ever, Centanni  and  Orta115  found  anopheles  larvae  in  water 
containing  8.77  per  1,000  of  sodium  chloride.  Ficalbi  and 
others115  found  them  in  water  containing  40  to  50  grams  of 
sodium  chloride  per  litre.     In  Algiers  and  the  Dutch  Indies 


76  THE   STUDY   OF   MALARIA 

anophelines  are  found  breeding  in  concentrated  sea-water,  and 
Banks116  found  M.  Ludlowii  breeding  in  sea-water  in  the  Phil- 
ippines. Bancroft  in  Queensland  found  a  species  of  anopheles 
breeding  in  sea-water,  and  at  Accra,  on  the  west  coast  of 
Africa,  Stephens  and  Christophers117  obtained  numerous  an- 
opheline  larvae  from  water  containing  6  per  cent,  of  salt.  De 
Vogel68  at  Semarang  found  certain  kinds  of  anopheles  breed- 
ing not  only  in  sea-water,  but  in  that  which  had  been  con- 
densed to  half  its  volume. 


Fig.  8. — A  raft  of  culex  ova. 

Ova  of  Anophelines. — These  mosquitoes  do  not  deposit 
their  eggs  in  a  raft-like  mass,  as  do  the  culex  (Fig.  8).  They 
are  laid  in  irregular  piles,  but  soon  become  scattered,  lie  hori- 
zontally, and  may  form  attractive  patterns  (Fig.  9)  upon  the 
surface  of  the  water.  In  captivity  the  eggs  may  be  laid  upon 
some  floating  object. 

The  ova  are  from  .7  to  1.0  mm.  in  length  by  about  .16  mm. 
in  breadth.    They  are  fusiform  in  shape  and  somewhat  broader 


Fig.  9. — Patterns  assumed  by  anopheles  ova.  Fig.  10. — Anopheles  ova. 

at  one  end  than  at  the  other.  The  lower  surface  is  convex, 
the  upper  nearly  flat.  From  the  middle  third  of  each  side 
protrudes  a  transversely  corrugated  membrane  which  acts  as 
a  float,  somewhat  after  the  manner  of  the  air  chambers  of 
a  lifeboat.  These  floats  are  said  to  be  absent  only  in  the  ova 
of  M.  turkhudi.  Around  the  margin  of  the  upper  surface  of 
the  ovum  is  a  frill,  usually  transversely  corrugated.  When 
first  laid  the  eggs  are  whitish,  but  soon  become  almost  black. 


Fig.    ii. — A  young  anopheles  larva.     Magnified. 


Fig.   12. — Half-grown  anopheles  larva.     Magnified. 


Fig.   14. — Anopheles  pupa.     Magnified. 


ETIOLOGY  77 

The  head  of  the  larva  lies  in  the  broad  end  of  the  egg  and 
escapes  by  loosening  a  circular  cap  from  this  end.  It  is  said 
that  if  an  ovum  is  partially  removed  from  the  water  the  broad 
end  always  hangs  downward  in  order  that  the  larva  may  be 
born  into  the  water  instead  of  into  the  air. 

The  duration  of  the  tgg  stage  varies  with  the  temperature, 
but  is  generally  from  two  to  four  days. 

Stephens  and  Christophers118  did  not  succeed  in  hatching  the 
ova  after  dessication  for  two  or  three  days,  but  Grassi116  is 
said  to  have  hatched  them  after  keeping  them  dry  for  twelve 
days. 

The  Larva. — The  head  of  the  anopheles  larva  (Fig.  13)  is 
more  or  less  globular;  the  eyes  are  situated  laterally  at  the 


Fig.  13. — Full-grown  anopheles  larva. 

broadest  part  of  the  head.  The  antennae  are  rod-shaped  and 
unjointed;  at  the  end  are  two  leaflets,  between  which  arises 
a  branched  hair.  The  mouth  parts  consist  of  the  feeding 
brushes  or  whorl-organs,  the  maxillary  palps,  the  mandibles, 
the  under  lip,  and  the  clypeus. 

The  neck  is  very  narrow  in  the  full-grown  larva. 

In  the  young  larva  (Fig.  11)  the  thorax  is  little,  if  any, 
wider  than  the  head,  but  in  older  specimens  it  is  much  wider. 

There  are  nine  post-thoracic  segments.  The  first  three  seg- 
ments bear  branched  lateral  hairs.  The  third  to  the  seventh 
segments  have  upon  the  dorsum  a  pair  of  fan-shaped  struc- 
tures, known  as  the  palmate  hairs  (Fig.  17). 

The  eighth  segment  contains  the  two  openings  of  the  respira- 
tory system,  which  ends  abruptly  at  the  dorsum  of  this  seg- 


78  THE   STUDY   OF  MALARIA 

ment  without  the  prolonged  breathing  tube  of  the  other  sub- 
families. 

The  ninth  or  caudal  segment  bears  four  flaps  containing 
respiratory  branchise.  This  segment  is  armed  with  two  large 
tufts  of  hair. 

The  color  of  the  larva  varies  greatly,  according  to  food  and 
environment,  and  may  be  grayish,  green,  almost  black,  reddish, 
or  mottled  with  black  or  white. 

The  full-grown  larva  is  about  8  mm.  in  length. 

Anopheline  larvae  are  omnivorous.  Their  diet  consists  of 
the  spores  of  algae,  diatoms,  animalcules,  bacilli,  other  larvae, 
moulted  skins,  mosquitoes,  and  other  small  insects.  In  cap- 
tivity they  eat  dry  rice  greedily. 

The  customary  location  of  these  larvae  is  at  the  surface  of 
the  water  near  the  edge  of  the  pool,  where  they  may  remain 
almost  motionless  for  long  periods.     The  characteristic  posi- 


Fig.  17. — A  palmate  hair. 

tion  is  parallel  with  the  surface  of  the  water  and  so  close  to  it 
that  a  portion  of  the  dorsum  appears  to  rise  above  the  surface, 
which,  however,  is  not  the  case.  When  feeding  the  constant 
motion  of  the  mouth  parts  creates  a  flow  of  water  toward  the 
mouth,  bringing  in  small  particles  of  food.  The  head  is  often 
rotated  suddenly,  so  that  it  turns  through  an  arc  of  180  de- 
grees, the  lower  surface  looking  uppermost.  On  taking  hold 
of  something  too  large  to  swallow  the  larva  will  often  shake 
the  head  vigorously  and  may  bend  the  body  to  steady  the 
particles  against  the  last  segments  of  the  body.  In  captivity 
they  often  rest  with  the  tail  against  the  sides  of  the  container 
and  the  head  toward  the  center,  when  numerous  forming  a 
fringe  around  the  circumference.  Locomotion  is  very  jerky 
and  irregular.  When  disturbed  they  not  infrequently  feign 
death.  From  the  behavior  of  the  anopheline  larvae  it  does  not 
appear  that  the  sense  of  sight  is  very  acute. 


Fig.   15. — Head  of  anopheles.     Magnified. 


Fig.   16. — Tail  of  anopheles  larva.     Magnified. 


Fig.   20. — Male  anopheles. 


Fig.   21. — Female,  anopheles. 


ETIOLOGY 


79 


Culex  larvae  have  been  thawed  out  of  ice  in  which  they 
were  imbedded  and  have  proceeded  to  develop  into  insects,  but 
so  far  as  the  writer  is  aware  this  has  not  been  done  with 
anopheles.     The  latter  have,  however,  been  found  in  water 


Fig.  1 8. — Adult  culex  larva. 

under  a  frozen  surface.     They  may  exist  for  a  few  hours  to  a 
few  days  upon  moist  mud. 

The  duration  of  the  larval  stage  varies  according  to  tem- 
perature, food,  and  possibly  other  conditions.  The  limits  may 
be  placed   at   from   ten   to   twenty-six   days.      In  warm   cli- 


Fig.  19.— Resting  positions  of  larvae  :  a,  Culex  ;   b,  anopheles. 

mates  when  suitable  food  is  abundant  the  duration  is  ordinarily 
twelve  or  fourteen  days.  In  cooler  climates  and  seasons  the 
duration  is  longer. 

Anopheles  and  culex  larvae  may  be  differentiated  by  the  fol- 
lowing gross  characteristics : 


80  THE   STUDY  OF   MALARIA 

Anopheles.  Culex. 

Habitually    at    the    surface    of    the  At  the  surface  to  breathe  only. 

water. 

Position  parallel  with   the   surface.  Hangs  at  an  agle  of  50  to  60  de- 
grees to  the  surface. 

No  respiratory  tube.  Large  respiratory  tube. 

In    full-grown    larvae    the    head    is  Relatively  larger  head. 

smaller  than  the  thorax. 

The  Pupa. — While  the  larva  bears  some  resemblance  to  the 
imago,  the  pupa  resembles  neither.  It  has  been  compared  in 
shape  to  a  hypertrophied  comma.  The  anopheles  resembles 
culex  more  closely  in  this  stage  than  in  any  other.  The  head 
and  thorax  are  enclosed  together  in  a  semitransparent  shell, 
through  which  portions  of  the  mouth  parts,  wings,  and  legs 
may  be  detected.  Respiration  is  no  longer  transacted  through 
the  eighth  abdominal  segment,  as  in  the  larva,  but  through  the 
trumpet-shaped  spiracles  or  syphons  of  the  thorax  (Fig.  27). 


Fig.  27. — Breathing  syphons  of  (a)  anopheles  and  (b)  culex  pupae. 

This  necessitates  a  change  in  position,  the  abdomen  hanging 
and  rather  curved  around  the  cephalo-thoracic  segment.  The 
eighth  abdominal  segment  bears  a  pair  of  broad  paddles  for 
locomotion.  The  young  pupa  is  rather  light  in  color,  but 
rapidly  becomes  darker. 

The  pupae  are  more  easily  alarmed  than  the  larvae,  and  when 
disturbed  dart  wildly  downward  with  rapid  jerks.  Being  of 
lower  specific  gravity  than  the  water,  they  rise  quickly  without 
effort.     They  do  not  eat. 

Italian  investigators115  observed  that  the  nymphae  of  some 
mosquitoes  resisted  freezing  and  dessication  to  a  remarkable 
degree.  Enclosed  for  several  hours  in  ice,  they  were  yet  able 
to  develop,  and  kept  in  dry  sOil  for  two  or  three  days  they 
developed  when  placed  in  water. 

The  duration  of  the  pupal  stage  is  ordinarily  from  two  to 
five  days. 


Fig.   22. — Young  culex  larva.     Magnified. 


Fig.   23. — Half-grown  culex  larva.     Magnified. 


Fig.  24. — Culex  pupa.     Magnified. 


Fig.   25. — Head  of  culex  larva.     Magnified. 


Fig.  26. — Tail  of  culex  larva.     Magnified. 


Fig.   28. — Male  culex. 


Fig.  29. — Female  culex. 


Fig.  30. — Young  stegomyia  larva.      Magnified. 


Fig.  31. — Grown  stegomyia  larva.     Magnified. 


Fig.  32. — Stegomyia  pupa.     Magnified. 


Fig-  33-— Head  of  stegomyia  larva.     Magnified. 


Fig-  34- — Tail  of  stegomyia  larva.     Magnified. 


Fig.  35. — Female  stegomyia. 


ETIOLOGY 


8l 


The  following  points  may  serve  to  distinguish  anopheles 
and  culex  pupse. 


Anopheles. 

Position  in  water  more  horizontal. 

Syphons  short,  square  truncated 
ends,  attached  to  middle  of 
thorax. 

Longer  anteroposteriorly,  nar- 
rower laterally. 


Culex. 
Position  more  vertical. 
Syphons  long  and  narrow,   slit-like 

opening,  attached  to  posterior  part 

of  thorax. 
Shorter  and  broader. 


When  approaching  the  emergence  of  the  imago  the  pupa  be- 
comes motionless  at  the  surface  of  the  water;  the  abdomen  is 
extended  parallel  with  the  surface ;  minute  air  bubbles  are  seen 
under  the  membrane,  which  then  splits  along  the  dorsal  line 
of  the  thorax.  The  imago  emerges  head  first,  then  the  thorax 
and  wings,  then  the  legs.  At  this  stage  the  insect  is  very  liable 
to  be  drowned  by  a  breeze  or  by  a  ripple  in  the  water. 


a-  ~b 

Fig.  36. — Heads  of  (a)  culex  and  (b)  anopheles  females. 

The  Imago. — The  head  is  subglobular  and  broader  than 
long.  The  compound  eyes  occupy  most  of  the  front  and  lateral 
portions  of  the  head. 

The  antennae,  composed  of  from  fourteen  to  sixteen  joints, 
arise  from  papillae  immediately  in  front  of  the  eyes,  scantily 
haired  in  females,  beautifully  plumose  in  males. 

The  proboscis  projects  from  the  middle  of  the  anterior 
margin  of  the  head  at  its  lowest  plane.  The  proboscis  is  highly 
complex.  It  is  composed  of  a  labrum  and  epipharynx,  a  hypo- 
pharynx,  two  mandibles,  two  maxillae,  and  a  labium  which 
forms  a  sheath  for  the  other  parts.  The  maxillae  and  mandi- 
bles serve  for  piercing  the  skin.     The  epipharynx  conducts  the 

6 


82 


THE   STUDY   OF   MALARIA 


blood  or  other  food  to  the  alimentary  canal.  Through  the 
hypopharynx  saliva,  containing  sporozoits  in  infected  mos- 
quitoes, is  injected. 

The  palpi  or  feelers  lie  to  either  side  and  somewhat  above 
the  proboscis.  In  anophelines  the  palpi  in  both  sexes  are  nearly 
as  long  as  the  proboscis,  and  are  clavate  in  the  male. 


Metatborax 
First  abdominal 
sejmenl" 


Abdomen 


Tibia\\    .\\        <3<^r~^ 

Basal  ~  %jf4  \\        \i  /^—^^ 

lobes  of -9       -  tt       ^,  Q<y^\ 

\        t  \  \ 

Basal 

•>      )     4  I     J\AaafoTsus\  -^. 

Gasper     — mb^  \v  \* 

ftttescis- ^  Head  of  Q        V.  \ 

8osol  lobesof  aVkm°S-  ^S ..  r°v 

FrortS: 'J 

Vertex -j- "^  \  ^^.Tartl 

Eyes 

Occiput"-. 

Nope -■ >g— ....     _^-  fjguw^ 

Fig.  37. — Diagram  of  mosquito  (after  Theobald). 

The  thorax  is  little  broader  than  the  head,  but  is  more  than 
twice  as  deep.  It  is  divided  somewhat  arbitrarily  into  three 
portions,  the  prothorax,  the  mesothorax,  and  the  metathorax, 
though  the  three  segments  are  fused  together  into  one.  From 
each  of  these  segments  arises  a  pair  of  legs.  But  little  of  the 
prothorax  is  visible  from  above,  a  small  lobe  projecting  from 
each  shoulder.     The  mesothorax,  comprising  the  bulk  of  the 


ETIOLOGY 


83 


thorax,  is  covered  by  the  scutum.  Behind  the  scutum  and  the 
origin  of  the  wings  is  the  transverse  scutellum,  behind  which 
is  the  metathorax  or  postscutellum. 

The  abdomen  is  larger  than  the  thorax,  depressed  being 
broader  than  deep,  and  is  composed  of  nine  segments.  The 
upper  and  under  surfaces  of  each  segment  are  somewhat  rigid ; 
laterally  the  membrane  is  softer  and  contains  the  openings  of 
ten  respiratory  tubes  or  stigmata.  The  anus  opens  ventrally 
upon  the  eighth  segment.  The  ninth  segment  bears  the  exter- 
nal organs  of  generation. 

The  legs,  six  in  number,  very  long  and  slender,  comprise 
the  following  joints:  The  coxa  and  trochanter,  the  femur,  the 
tibia,  and  the  five-jointed  tarsus,  the  distal  joint  of  which  bears 
the  claws. 

The  wings  originate  from  the  posterior  portion  of  the  meso- 
thorax.    The  wing  venation  is  best  understood  by  referring  to 


HUMtRW.C«)SSrtW 

.■■hnsTO.VFlH 


^VEIR         «<?\tm  3"SVE1H 

/     -hVEm  /        pmif  lOfJBSUBWRGIHALCai 


Fig.  38. — Diagram  of  the  wing  of  a  mosquito  {Culex  pipiens),  with  names  of  veins, 
cells,  etc.  (Coquillett). 


the  illustration  (Fig.  38).  The  wing  scales  are  of  importance 
in  classification. 

From  the  metathorax  arises  the  pair  of  halteres  or  balancers, 
club-shaped  organs,  rudiments  of  a  second  pair  of  wings.  Sup- 
plied with  one  of  the  largest  nerves  of  the  body,  they  are  re- 
garded as  sense  organs. 

Anopheles  is  distinguished  from  culex  especially  by  the  palpi, 
which  in  the  former  is  in  both  sexes  almost  as  long  as  the 
proboscis,  in  the  latter  the  palpi  of  the  female  being  very  short. 
Anopheles  is  more  slender,  the  head  is  smaller,  and  the  legs 


84  THE   STUDY  OF  MALARIA 

more  delicate.  The  palpi  of  the  female  being  thickly  scaled 
and  lying  close  to  the  proboscis  give  the  impression  of  a  thick 
beak,  which  contrasts  strongly  with  the  short  palpi  and  slender 
proboscis  of  the  culex.  The  wings  of  the  anopheles  are 
speckled,  which  is  not  the  case  with  any  of  the  common  species 
of  culex. 

The  sitting  position  of  anopheles  is  characteristic.  The 
body  of  the  insect  is  at  an  angle  with  the  surface  upon  which  it 
rests,  the  proboscis  pointing  toward  the  surface,  sometimes 
even  touching  it.  This  angle  varies  in  different  anopheline 
species,  in  some  being  almost  a  right  angle,  when  the  insect 
appears  almost  like  standing  upon  its  head.  The  proboscis, 
head,  thorax,  and  abdomen  are  in  the  same  line.  The  mosquito 
at  rest  has  been  compared  to  a  brad-awl  stuck  into  the  wall. 
It  often  rests  upon  the  first  two  pairs  of  legs,  waving  the  last 


Fig.  39. — Resting  positions  of  (a)  anopheles  and  (b)  culex. 

pair  in  the  air.  Culex  at  rest  is  angular  and  humpbacked. 
Stegomyia  may  be  recognized  by  its  smooth,  velvety  coat  of 
jet  black  and  silvery  white,  the  banded  legs  and  abdomen,  and 
the  lyre-shaped  ornamentation  of  the  thorax. 

The  three  commonest  species  of  anophelines  of  the  United 
States  are  thus  described  by  Giles  :119 

Anopheles  Maculipennis  (Meigen). — "Wings  with  four 
tufted  spots  on  the  wing-field,  the  costa  being  uniformly  dark 
except  at  the  apex,  where  its  color  fades  to  form  a  fairly  dis- 
tinct spot;  tarsi  unhanded,  but  with  an  apical  yellowish  spot 
to  the  first  joints.  Thorax  with  four  broad  ferruginous  stripes 
formed  of  golden  hairs,  between  which  the  darker  ground  color 
is  left  bare,  with  a  tuft  of  large  golden  scales  on  the  anterior 
border.  Abdominal  segments  brown  with  yellowish  basal 
markings ;  anterior  femora  not  thickened  at  the  base. 


ETIOLOGY  85 

"Female. — Head  with  two  patches  of  creamy  scales  divided 
by  a  central  line,  the  rest  of  the  head  with  black  scales,  a  small 
tuft  of  white  hairs  in  front;  borders  of  the  eyes  white;  eyes 
deep  purplish-black ;  antennae  dark  brown  with  pale  bands  and 
with  ferruginous  basal  joint,  pale  pubescence,  and  brown  hairs; 
proboscis  brown ;  palpi  yellowish-brown  with  dense,  dark  scales 
at  the  base,  which  is  swollen,  shorter  than  the  proboscis.  Legs 
with  pale  coxae ;  femora  and  tibiae  yellowish-brown  below,  cov- 
ered with  dark-brown  scales  above;  knee  spot  yellow,  apex  of 
the  tibiae  paler ;  tarsi  slightly  darker  than  the  rest  of  the  leg. 

"Male. — Antennae  banded,  plume  hairs  brown,  last  joint 
darker ;  proboscis  black  to  dark  brown ;  palpi  dark  brown ;  the 
last  two  joints,  which  are  clubbed,  have  a  number  of  short 
golden  hairs  internally  and  are  yellow  in  color,  clothed  with 
thick  black  scales,  through  which  the  yellow  underground 
shows;  the  last  joint  is  truncated.  Length  4  to  7.5  mm.  male, 
to  8  or  10  mm.  female.  This  species  varies  greatly  in  size,  the 
wings  shown  me  in  Italy  by  Professor  Grassi  being  quite  small, 
while  some  Canadian  specimens  in  the  British  Museum  are 
huge  gnats,  and  to  illustrate  this  I  have  superposed  on  the 
plate  the  drawing  of  one  of  Grassi's  specimens  on  the  outline 
of  a  Canadian  specimen." 

Anopheles  Punctipennis  (Say.). — "Wings  with  the  costa 
black,  interrupted  by  a  single  large  ferruginous  spot  a  little 
outside  the  transverse  veins,  and  involving  the  first  and  second 
longitudinal  veins.  There  is  also  a  small  apical  spot,  and  some 
yellow  spots  near  the  tips  of  the  long  veins,  but  otherwise  the 
wing  is  very  dark  and  has  no  interruptions  of  the  fringe.  Legs 
and  tarsi  uniformly  nearly  black.  Thorax  and  abdomen  deep 
brown,  nude  but  for  some  yellowish-brown  hairs.  Wings 
much  longer  than  abdomen. 

"Head  black  with  scanty  whitish  frontal  tuft.  Palpi  and 
proboscis  dark  yellowish-brown,  unhanded  but  rather  lighter  at 
the  tips.  Halteres  brown.  This  is  not  likely  to  be  confused 
with  any  other  species  than  my  An.  gigas,  but  may  be  distin- 
guished by  the  base  of  the  wing  internal  to  the  large  spot  being 
uniformly  black  instead  of  spotted  with  yellow,  as  in  gigas,  as 
well  as  its  being  altogether  a  darker  species.     There  appears 


86  THE   STUDY   OF  MALARIA 

to  be  a  triangular  swelling  at  the  base  of  the  abdominal  seg- 
ments. It  may  be  distinguished  from  An.  crucians  by  the  costa 
of  the  latter  being  uniformly  dark  and  by  its  having  two  instead 
of  three  dark  spots  on  the  sixth  longitudinal  vein.  The  middle 
spot  extends  much  further  across  the  wTing  than  in  the  Sinensis 
group,  and  the  tarsi  are  unbanded.    Length  5  to  7  mm." 

Anopheles  Crucians  (Wied.). — "Wings  with  white  spots 
here  and  there  on  the  brown  veins,  uniform  along  the  costa; 
tarsi  unbanded,  dusky  brown ;  abdomen  uniformly  brown  with 
grey  hairs.  .  Thorax  red-brown  with  linear  markings. 

"Description  from  Wied.,  A.  Z.  I.,  p.  12  :  'Tawny;  the  thorax 
with  three  deeper-tinted  lines ;  the  abdomen  covered  with  grey 
hairs ;  the  wings  with  dusky  spots  and  costa.  Length  2j/>  lines 
(German).' 

"Coquillett,  in  his  recent  synoptic  table  of  North  American 
Culicidce,  states  that  'the  scales  of  the  last  veins  are  white, 
marked  with  three  black  spots ;  palpi  marked  with  white  at  the 
bases  of  the  last  four  joints,'  and  without  any  spot  on  the 
costa,  as  seen  in  A.  punctipennis. 

"Professor  Nuttall  sent  Mr.  Theobald  two  females  from 
America  in  spirit,  which,  although  much  damaged,  show  the 
two  features  mentioned  by  Coquillett  very  clearly,  readily  dis- 
tinguishing the  species  from  the  C.  punctipennis  of  Say." 

The  following  key  to  the  mosquitoes  of  North  and  Middle 
America  is  that  of  Air.  Coquillett,120  of  the  Department  of 
Agriculture,  by  whose  kind  permission  it  is  here  reproduced : 


A    CLASSIFICATION    OF   THE    MOSQUITOES   OF  NORTH   AND    MIDDLE 
'  AMERICA 

Table  of  the  Subfamilies 

A.  Scutellum  convex  behind,  never  distinctly  three-lobed ;  posterior  end  of 

the  thorax  bare ;  small  cross-vein 
usually  situated  considerably  before 
the  root  of  the  third  vein  and  con- 
nected with  it  by  a  stump  of  a  vein; 
claws  of  the  female  simple. 
B.  Proboscis  straight  or  almost  so ;  back  of  the  head  devoid  of 

broad  appressed  scales,  but  with  many 
narrow  outstanding  ones ;  body  never 
with  metalescent  scales ;  first  sub- 
marginal  cell  longer  than  its  petiole; 
claws  simple  in  both  sexes. 


ETIOLOGY  87 

1.  ANOPHELIN/E 

BB.  Proboscis  strongly  decurved ;  back  of  the  head  wholly  covered 

with  broad  appressed  scales,  but  de- 
void of  narrow,  outstanding  ones ; 
body  covered  with  broad  appressed 
metalscent  scales;  first  submarginal 
cell  less  than  half  as  long  as  its 
petiole;  some  of  the  claws  of  the 
male  toothed. 

2.  Megarhinin.* 

AA.  Scutellum    distinctly    three-lobed;    small    cross-vein    usually    situated 

beyond  the  root  of  the  third  vein. 
C.  Posterior  end  of  the  thorax  bare. 

D.  First  submarginal  cell  at  least  nearly  as  long  as  its 
petiole ;  some  of  the  claws  of  the 
male  toothed;  thorax  never  with 
metallic  bluish  scales  arranged  in 
lines  or  spots. 
E.  Second  joint  of  the  antennae  less  than  eight 
times  as  long  as  wide  in  both  sexes, 
with  many  long  hairs,  longer  and 
more  numerous  in  the  male. 
F.  Femora  bearing  many  outstanding  scales ; 
wing  scales  narrow. 

3.  PSOROPHORIN^E 

FF.  Femora  devoid  of  outstanding  scales.1 

4.  CULICIINLE 

EE.  Second  joint  of  the  antennae  unusually  long,  in 
both  sexes  over  fourteen  times  as 
long  as  wide;  antennae  in  both  sexes 
with  a  few  short  hairs  only. 

5.  Deinoceritin^e 

DD.  First  submarginal  cell  less  than  half  as  long  as  its 
petiole ;  claws  simple  in  both  sexes ; 
thorax  with  metallic  bluish  scales 
which   form   lines   or   spots. 

6.  Uranotveniiinle 

CC.  Posterior  end  of  the  thorax  behind  the   scutellum  bearing 

several  bristles  and  sometimes  with 
a  few  scales ;  claws  simple  in  both 
sexes ;  antennae  similar  in  the  two 
sexes,  bearing  many  long  hairs. 

7.  Trichoprosoponin^e 

1.     Subfamily  ANOPHELINjE  Theobald 
Table  of  the  Genera 

1.  Abdomen  with  clusters  of  broad,   outstanding  scales   along  the  sides ; 

outstanding  scales  on  the  veins  of  the  wings  chiefly  rather  broad. . .  4 
Abdomen  never  with  such  clusters  of  scales • •  2 

2.  Outstanding  scales   on  the  veins  of  the  wings  lanceolate,  or  broader, 

strongly  tapering  to  their  bases ;  V*  *:; ',," •'  3 

Outstanding  scales  very  narrow,  linear,  very  slightly,  if  at  all    tapering 
to  their  bases ;  feet  with  white  bands.     (Middle  America)  .  .Mysomyta 
■?   Veins  of  the  wings  having  the  outstanding  scales  rather  narrow,  lanceo- 
late ;  feet  wholly  black •  •  •  •  •  ■Anopheles 

Veins  of  the  wings  with  many  broad,  obovate,  outstanding  scales ;  teet 
with  narrow,  indistinct  white  bands  at  the  bases  of  some  of  the 
joints.     (Middle  America) Cycloleppteron 

'Except  in  the  genus  Aedeomyia,  which  has  broad  wing  scales. 


88  THE   STUDY  OP   MALARIA 

4.  Upper  side  of  thorax  and  scutellum  bearing  many  appressed  lanceolate 
scales ;  outstanding  scales  on  the  veins  of  the  wings  rather  narrow, 

lanceolate.     (Florida   and   southward) Cellia 

Upper  side  of  thorax  and  scutellum  with  hairs  only ;  many  rather  broad, 
obovate  outstanding  scales  on  the  veins  of  the  wings.  (Middle 
America) Nototricha  n.  gen. 

Genus  MYZOMYIA  Blanchard 

(Synonym:   Grassia  Theobald) 

Wings  black-scaled  and  with  several  white-scaled  patches ;  feet  black, 
banded  with  white;  thorax  gray  and  with  four  black  stripes.  (West 
Indies ) lutsii   Theob. 

Genus  ANOPHELES  Meigen 
(a)  Table  of  the  Species 

1.  Wings  marked  with  spots  of  dark  or  light-colored  scales 2 

Wings  unspotted;  length  of  the  head  and  body  about  3  mm. 

barberi  Coq. 

2.  Front  margin  of  the  wings  with  a  patch  of  whitish  scales  at  a  point 

about  three-fourths  of  the  way  from  base  to  apex  of  the  wing. . . .   S 
Front  margin  of  the  wings  wholly  black-scaled 3 

3.  Sixth,  or  last,  vein  of  the  wings  wholly  black-scaled 4 

Sixth  vein  white-scaled  and  with  three  patches  of  black  scales. 

crucians  Wied. 

4.  Hind  tibise  yellowish-white-scaled  on  the  apical   fourth;   first  vein  of 

the  wings  with  a  patch  of  yellow  scales  before  its  middle  and  another 

on  the  apex.     (Central  America) eiseni  Coq. 

Hind  tibiae  narrowly  yellowish-white  scaled  at  the  extreme  apex  only, 
first  and  other  veins  with  black  scales  only maculipennis  Meig. 

5.  Scales  of  the  last  vein  of  the  wings  white,  those  at  its  apex  black; 

third  vein  white-scaled  and  with  two  patches  of  black  scales 6 

Scales  of  the  last  vein  white,  those  at  each  end  black;  third  vein  black- 
scaled,  the  extreme  apex  white-scaled punctipennis  Say. 

6.  Fourth  vein  of  the  wings  black-scaled,   the   apices   of  the   forks   and 

usually  also  a  patch  at  the  cross  veins  white-scaled. 

franciscanus  McC. 

Fourth  vein  white-scaled,  the  forks  (except  their  apices)  and  on  either 

side  of  the  cross  veins  black-scaled pseudopunctipennis  Theob. 

(b)  List  of  the  Species  and  Synonyms 

barberi  Coq.  maculipennis  Meig. 

crucians  Wied.  annulimanus  van  der  Wulp.1 

eiseni  Coq.  bifurcatus    Meigen    (1804;    not    of 

franciscanus  McCracken.  Linne,  1758). 

quadrimaculatus  Say. 
pseudopunctipennis  Theob. 
punctipennis  Say. 
hyemalis  Fitch. 

(c)  Unrecognized  Species 

bifurcatus  Linne,  nigripes  Stseger,  and  walkeri  Theobald.  These  species 
are  said  to  have  unspotted  wings,  like  barberi,  but  are  larger,  have  yellow 
scales  on  the  thorax,  etc. 

pictus  Loew.  This  species,  described  from  Asia  Minor,  was  also  re- 
corded from  North  America  by  its  author,  but  he  evidently  mistook  some 

\A.t  my  request  Dr.  C.  Ritsema  Cz  compared  specimens  of  maculipennis 
with  the  type  of  annulimanus  in  the  Leyden  Museum,  and  informed  me 
that  they  are  identical. 


ETIOLOGY  89 

other  species  for  it.     No  specimen  of  his  species  has  been  reported  from 
this  country  since  the  time  he  published  the  statement. 

quinquefasciatus    Say    (ferrugtnosus    Wied.).     This    is    a    synonym    of 
Culex  pipiens  L. 

Genus  CYCLOLEPPTERON  Theobald 

Thorax  with  a  velvety  black  dot  near  the  middle  of  either  side;  feet 
almost  unicolorous,  not  distinctly  banded ;  wing  scales  chiefly  brown 
or  black,  a  patch  of  yellow  ones  at  a  point  about  two-thirds  the 
length   of  the   front  margin  and   four   smaller   ones  at  the  apex  of 

the  wing   grabhami  Theob. 

(C.  medio punctatus  Theob.  belongs  to  the  following  genus.) 

Genus  NOTOTRICHA,  New  Genus 

Thorax  with  a  velvety  black  dot  near  the  middle  of  either  side  and  a 
larger  spot  in  front  of  and  extending  upon  the  scutellum;  legs 
brown-scaled  and  with  many  dots  and  narrow  bands  of  light-colored 
scales mediopunctata  Theob. 

Genus  CELLIA  Theobald 

(Synonym:  Arribalzagia  Theobald) 

(a)   Table  of  the  Species 

1.  Hind    feet    from   the    middle    of    the    second    joint    largely    or   wholly 

snow-white     2 

Hind   feet  black,   mottled   with   whitish   and  with  bands   of   the   same 
color  at  the  sutures  of  the  joints maculipes  Theob. 

2.  With  a  black  band  at  the  base  of  the  last  joint  of  each  hind  foot. 

albimanus  Wied. 
Without  such  a  band argyritarsis  Desv. 

(&)  List  of  the   Species   and   Synonyms 

albimanus  Wied.  argyritarsis  Desv. 

albipes  Theob.  albitarsis  Arrib. 

cuber  sis  Agramonte.  maculipes  Theob. 
tarsimaculatus  Goeldi. 

2.    Subfamily  MEGARHINESLE  Theobald 
(Synonym:    Lynchiellina   Lahille) 

Genus  MEGARHNINUS  Desvoidy 
(Synonym:  Lynchiella  Lahille) 

(a)  Table  of  the  Species 

1.  Feet  with  a  white  band,  at  least  on  the  hind  ones;  middle  joint  of  the 

male  palpi  with  many  yellow  scales  on  the  outer  side;  hairs  of  the 

male  antennae  long  and  dense 2 

Feet  wholly  black  on  at  least  their  upperside ;  palpi  wholly  purple-scaled ; 
hairs  of  the  male  antennae  rather  short  and  sparse.     (West  Indies.) 

violaceus  Wied. 

2.  Middle  and  front  feet  wholly  black portoricensis  Roeder 

Middle  and  usually  the  front  feet  with  a  white  band  on  each. 

rutilus  Coq. 

(b)  List  of  the  Species  and  Synonyms 

portoricensis  Roeder.  violaceus  Wied. 

ferox  Walker  (not  of  Wiedemann).         purpureus  Theob. 
rutilus  Coq. 


9<D  THE   STUDY   OF   MALARIA 

(c)  Unrecognized  Species 

grandiosus  Will.,  hcemorrhoidalis  Fab.,  and  longipes  Theob.     These  three 
species  have  been  reported  from  Mexico. 

3.    Subfamily  PSOROPHORIN^E  Mitchell 

Genus  PSOROPHORA  Desvoidy 

(Synonym:   Chrysoconops  Goeldi) 

(a)  Table  of  the  Species 

1.  Abdomen  yellow   or  brownish,  its   scales  yellowish 3 

Abdomen   black,    its    scales    chiefly   purple;    upper    side   of   the   thorax 

polished  black,  usually  white-scaled  toward  the  sides 2 

2.  Front  and  middle  femora  black,  their  scales  purple  except  at  the  narrow 

apex  of  each  femur,  where  they  are  white.     (Middle  America.) 

cilipes  Fab. 
Front  and  other  femora  yellow,  yellow-scaled,  their  broad  apices  black- 
scaled   howardii  Coq. 

3.  Veins  in  the  front  half  of  the  wings,  except  toward  their  apices,  deep 

yellow,  their  scales  of  the  same  color,  scales  on  the  front  half  of  the 

thorax  golden  yellow.     (West  Indies) fulva  Wied. 

Veins  and  scales  of  the  wings  wholly  brown,  scales  in  the  middle  of  the 
upper  side  of  the  thorax  golden  yellow,  those  toward  the  sides  white. 

ciliata  Fab. 

(b)  List  of  the  Species  and   Synonyms 

ciliata  Fab.  fulva  Wied. 

conterrens  Walk.  flavicosta  Walk. 

molestus  Wied.  ochripes  Macq. 

perterrens  Walk.  howardii  Coq. 

rubidus  Desv. 
cilipes  Fab. 

(c)  Unrecognized  Species 
scintillans  Walk.     This  species  has  been  recorded  from  the  West  Indies. 

4.    Subfamily  CULICIN^  Theobald 

(Synonyms:  Aedeomyince  Theobald,  Hcemagogince  Lutz) 

Table  of  the  Genera 

1.  Claws  of  the  female  toothed  on  at  least  the  front  and  middle  feet; 

some  of  the  claws  of  the  male  also  toothed 4 

Claws  of  the  female  simple 2 

2.  Palpi  of  the  male  at  least  three-fourths  as  long  as  the  proboscis 10 

Palpi  of  the  male  at  most  only  one-half  as  long  as  the  proboscis.  (Mid- 
dle   America) 3 

3.  Head  posteriorly  with  very  narrow  scales  and  with  a  patch  of  broad 

ones  on  each  side 18 

Head  sparsely  or  densely  covered  with  broad  scales  posteriorly 21 

4.  Scales  along  the  sides  of  the  upper  surface  of  the  thorax  narrow, 

almost  linear,  legs  never  with  outstanding  scales 6 

Scales  along  the  sides  of  the  upper  surface  of  the  thorax  chiefly  rather 
broad,  obovate,  hind  part  of  the  head  with  many  similar  scales  scat- 
tered   about .•  •     5 

5.  Legs  devoid  of  outstanding  scales Lepidosia 

Legs  bearing  many  outstanding  scales,  at  least  on  the  hind  feet,  all  feet 

black,  the  hind  ones  alone  partly  white Janthinosoma 


ETIOLOGY 


91 


6.  Back  part  of  the  head  densely  covered  with  broad,  appressed  scales 

except  sometimes  a  narrow  stripe  in  the  middle 7 

Back  part  of  the  head  sparsely  covered  with  narrow,  almost  linear 
scales  and  with  a  patch  of  broad  ones  on  each  side 8 

7.  Clypeus  bearing  several  scales  or  hairs,   scutellum  with  broad  scales 

only  Stegomyia 

Clypeus  bare,  scutellum  with  narrow  scales  only.     (Middle  America.) 

Verrallina 

8.  Wing  veins   having   the    outstanding   scales    narrow,    lanceolate,    only 

slightly  tapering  to  the  base 9 

Wing  veins  having  many  very  broad  outstanding  scales  which  taper 
strongly  to  their  bases ;  several  of  the  scales  are  hollowed  out  at 
their  apices Lepidoplatys 

9.  Palpi  of  the  male  less  than  one-fourth  as  long  as  the  proboscis.  .Aedes 
Palpi  of  the  male  about  as  long  as  the  proboscis Ochlerotatus 

10.  Head  densely  covered  behind  with  broad,  appressed  scales,  except  a 

narrow  stripe  in  the  middle,   or   else  the  thorax   has   six  lines   of 

silvery   scales 23 

Head  bearing  narrow,  almost  linear  appressed  scales  behind  and  with 
a  patch  of  broad  ones  on  each  side ;  thorax  never  with  lines  of 
silvery   scales 11 

11.  Outstanding  scales  on  the  veins  behind  the  first  one  narrow  and  of 

nearly  a  uniform  width 12 

Outstanding  scales  on  at  least  the  apical  half  of  the  wings  broad,  con- 
siderably narrowed  at  their  bases 17 

12.  Feet  white  at  each  end  of  some  of  the  joints  or  else  wholly  black, 

in  which  case  the  abdomen  is  wholly  black-scaled,  or  else  it  has  cross- 
bands  of  light-colored  scales 13 

Feet  white  at  the  bases  only  of  some  of  the  joints,  or  else  wholly 
black,  in  which  case  the  abdomen  is  black-scaled  and  with  the  front 
corners  of  some  of  the  segments  white-scaled Grabhamia 

13.  Costa  of  the  wings  not  spotted 14 

Costa  black-scaled  and  with  three  large  spots  of  pale  yellow   scales. 

(Middle    America) Lutzia 

14.  Thorax  with  two  distinct  bare  stripes  near  the  middle  of  the  upper 

side;  hind  cross-vein  at  least  its  own  length  from  the  small  cross 

vein    Culicella 

Thorax  without  bare   stripes 15 

15.  Scales  of  the  wings  collected  into   spots ;   hind  cross-vein  much  less 

than  its  length  from  the  small  cross-vein Theobaldia 

Scales  of  the  wings  uniformly  distributed 16 

16.  Hind  cross-vein  much  less  than  its  own  length  from  the  small  cross- 

vein   Culiseta 

Hind  cross-vein  situated  at  least  nearly  its  own  length  from  the  small 
cross-vein Culex 

17.  Basal  half  of  the  wings  having  the  outstanding  scales  of  the  veins  nar- 

row and  almost  linear;  proboscis  wholly  black Melanoconion 

Basal  half  of  the  wings  having  many  broad,  outstanding  scales  on  the 
veins     20 

18.  Wing  veins  having  the  outstanding  scales  narrow,  almost  linear. ...   19 
Wing  veins  having  the  outstanding  scales  rather  broad,  oblanceolate ; 

palpi  of  the  male  almost  one-half,  those  of  the  female  less  than  one- 
fifth,  as  long  as  the  proboscis Tinolcstes 

19.  Palpi  in  both  sexes  about  one-third  as  long  as  the  proboscis .  .Micraedes 
Palpi  in  both  sexes  less  than  one-fifth  as  long  as  the  proboscis. 

Isostomyia  n.  gen. 

20.  The  outstanding  scales   on  the  veins   of  the  wings   only   moderately 

broad,  over  twice  as  long  as  broad,  their  apices  rounded ;  proboscis 

and  feet  usually  with  light-colored  bands Coquillettidia 

The  outstanding  scales  chiefly  unusually  broad,  their  apices  flat  or 
hollowed   out Tceniorhynchus 


92  THE   STUDY   OF  MALARIA 

21.  Outstanding  scales  on  the  wing  veins  unusually  broad ;  femora  toward 

their  apices  bearing  several  elongate,  outstanding  scales ;  body  devoid 

of  blue  scales    Aedeomyia 

Outstanding  scales  on  the  wing  veins  narrow,  almost  linear,  legs  devoid 
of  outstanding  scales,  head  and  body  chiefly  blue  scaled 22 

22.  Base  of  the  first  submarginal  cell  nearer  to  the  base  of  the  wing  than 

is  that  of  the  second  posterior  cell;  palpi  of  the  male  less  than  one- 
fifth  as  long  as  the  proboscis,  the  abdomen  bearing  only  a  few  hairs 

on  the  under  side  of  the  penultimate  segment Hazmagogus 

Base  of  the  first  submarginal  cell  noticeably  nearer  to  the  apex  of  the 
wing  than  is  the  base  of  the  second  posterior  cell;  palpi  of  the 
male  about  one-half  as  long  as  the  proboscis;  abdomen  of  the  male 
with  a  large  cluster  of  outstanding,  blunt  spines  on  the  under  side 
of  the  penultimate  segment Cacomyia  n.  gen. 

23.  Scutellum  bearing  both  broad  and  narrow  scales ;  head  behind  covered 

with  broad  appressed  scales  except  a  median  stripe  of  rather  narrow 
ones;    outstanding    scales    on    the    wing    veins    narrow.       (Middle 

America) Gymnometopa 

Scutellum  with  narrow  scales  only 24 

24.  Back  of  the  head  covered  with  broad  appressed  scales  except  a  median 

stripe  of  rather  narrow  ones;  outstanding  scales  on  the  wing  veins 

narrow.     (Middle  America)    Howardina 

Back  of  the  head  with  narrow  scales  only;  many  rather  broad,  out- 
standing scales  on  the  wing  veins Pneumaculex 

Genus  LEPIDOSIA  Coquillett 

Our  two  species  have  the  scales  of  the  abdomen  deep  blue,  except  those 
of  the  first  segment  and  a  broad,  usually  interrupted  band  on  the 
apices  of  the  other  segments,  which  are  pale  yellow  or  whitish. 

Hind  feet  wholly  black cyanescens  Coq. 

Hind  feet  black,  the  last  joint  white mexicana  Bell. 

Genus  JANTHINOSOMA  Arribalzaga 

(Synonym:  Conchyliastes  Theobald) 

(a)  Table  of  the  Species 

1.  Last  two  joints  of  the  feet  wholly  white 3 

Last  joint  largely  or  wholly  black,  the  preceding  joint  chiefly  white..  2 

2.  Scales  on  the  upper  side  of  the  thorax  yellow varipes  Coq. 

Scales  brown,  those  toward  the  sides  yellow discrucians  Walk. 

3.  Upper   side   of   the  thorax  yellow-scaled  and   with   a  broad   stripe   of 

brown  scales  in  the  middle lutsii  Theob. 

Upper  side  of  the  thorax  wholly  yellow-scaled posticata  Wied. 

(b)  List  of  the  Species  and  Synonyms. 

discrucians    Walker    (not    of    Giles  posticata  Wiedemann  (not  of  Theo- 

and  Theobald).1  bald). 

arribalsagcB  Giles.  musica  Say. 

lutzii  Theob.  varipes  Coq. 

albitarsis  Neveu-Lemaire   (not  of  johnstonii  Grabham. 
Theobald). 

discrucians    Giles    and    Theobald 
(not  of  Walker). 

1  The  form  referred  to  this  species  by  these  two  authors  has  the  entire 

apex   of  the  hind   feet  wholly  white,  whereas   in   his   original   description 

Walker  expressly  states,  both  in  the  Latin  diagnosis  and  in  the  English 
description,  that  there  is  only  a  subapical  white  band  in  discrucians,  the 
remainder  of  the  feet  being  purple. 


ETIOLOGY 


93 


(c)  Unrecognized  Species 
terminate    Coquillett    (posticata    Theobald,    not    of    Wiedemann)     was 
described    from    St.    Lucia,   W.   Ind.,   and   differs    from   all   of   the' other 
species  in  that  the  last  joint  only  of  the  hind  feet  is  white. 

Genus  STEGOMYIA  Theobald 

(a)  Table  of  the  Species 

Thorax  marked  with  a  pair  of  curved  silvery  stripes   forming  a  figure 

which  somewhat  resembles  a  lyre;  proboscis  unicolorous  black    feet 

black  and  with  white  bands  at  the  bases  of  some  of  the  joints. 

calopus  Meig. 

(b)  List  of  the  Species  and  Synonyms 

calopus  Meig.  calopus  Meig— Continued 
annuhtarsis  Macq.  konoupi  Brulle. 

bancroftii  Skuse.  luciensis  Theob. 

elegans  Ficalbi.  mosquito  Desv. 

exagitans  Walk.  queenslandensis  Theob. 

exatans   Walk.  rossa  Giles. 

fasaata  Fab.  tmiiatus  Wied. 

formosa  Walk  toxorhynchus  Macq. 

frater^  Desv.  viridifrons  Walk. 

impatibite  Walk.  sonatipes  Walk 
mexorabite  Walk. 
(S.  sexlineata  Theob.  belongs  to  the  genus  Gymnometopa.) 

Genus  VERRALLINA  Theobald 

Upper  side  of  the  thorax  black-scaled,  the   sides   in   front  of  the  wings 

white-scaled insoUta  C(f 

Upper  side  of  the  thorax  wholly  whitish-scaled latemaria  Coq. 

Genus  LEPIDOPLATYS  Coquillett 
(a)  Table  of  the  Species 

Scales  of  the  wings  mixed  brown  and  white;  feet  with  broad  white  bands 
at  the  bases  of  some  of  the  joints,  tibiae  not  distinctly  banded. 

squamiger  Coq. 

(b)  List  of  the  Species  and  Synonyms 
squamiger  Coq. 
deniedmannii  Ludlow. 

Genus  AEDES  Wiedemann1 
Upper  side  of  the  thorax  golden-yellow  scaled ;  abdomen  black-scaled  and 
with  a  band  of  yellow  scales   at  the   bases   of  the  segments ;    feet 

unicolorous  black.       fuscus  Q    s> 

(A.  smitlni  belongs  to  Wyeo myia. ) 

Genus  OCHLEROTATUS  Arribalzaga 

(Synonyms:  Cu licada  Felt,  Culicelsa  Felt,  Ecculex  Felt,  Protoculex 
belt,  Pseudoculex  Dyar.) 

'This  genus  has  commonly  been  credited  to  Meigen,  but  he  expressly 
states_  that  he  had  not  seen  a  specimen  and  that  both  the  name  and  de- 
scription had  been  furnished  to  him  by  Wiedemann 


94  THE   STUDY   OF   MALARIA 

(a)  Table  of  the  Species 

i.  Ground  color  of  the  thorax  bright  yellow;  the  scales  and  bristles  of 

the  head  and  thorax  wholly  yellow   2 

Ground  color  of  the  thorax  brown  or  black 3 

2.  With  an  ovate  black  spot  above  the  insertion  of  _ each  wing;  feet  not 

distinctly  two-colored,  claws  of  the  hind  ones  simple. 

bimaculatus  Coq. 

Without  such  a  spot;  feet  dark  colored  and  with  white  bands  at  the 

bases  of  some  of  the  joints.     (Middle  America) knabi  Coq. 

3.  Feet  dark  colored  and  with  white  bands 19 

Feet  not  distinctly  banded,  proboscis  unhanded ._ 4 

4.  Scales  of  the  abdomen  black,  sometimes  a  crossband  or  pair  of  spots 

of  light-colored  scales  on  some  or  all  of  the  segments 5 

Scales  of  the  abdomen  yellow,  except  a  pair  of  spots  of  black  ones 
on  some  of  the  segments;  claws  toothed  on  all  of  the  feet  in  the 
female  spenceri  Theob. 

5.  Light-colored  scales  of  the  abdomen  forming  crossbands   situated  at 

the  bases  of  the  segments ; 6 

Light-colored  scales,  when  present,  forming  spots  en  the  sides  of  some 
of  the  segments   _ l4 

6.  Upper  side  of  the  thorax  yellow-scaled  and  with  three  stripes  of  brown 

scales;  scales  of  the  wings  wholly  brown;  all  the  claws  of _ the  female 

toothed  trivittatus  Coq. 

Upper  side  of  the  thorax  not  marked  like  this _ 7 

7.  Thorax  with  a  brown-scaled  stripe  along  the  sides  and  with  a  wider 

space  of  white  scales  in  the  middle;   scales   of   the  wings   wholly 

brown ;  all  of  the  claws  toothed  in  the  female dupreei  Coq. 

Thorax  not  marked  in  this  manner 8 

8.  Sides  broadly  and  the  front  end  of  the  thorax  whitish-scaled;  back 

part    of    the    head    also    whitish-scaled;    all    claws    toothed    in    the 

female   •  •     9 

Sides  and  front  end  of  the  thorax  yellow  or  brown  scaled 10 

9.  Middle  of  the  thorax  with  a  broad  stripe  of  brown  scales. 

pretans  Grossb. 
Middle  of  the  thorax  having  the  scales  yellow  and  whitish. 

cinereoborealis  Felt. 

10.  The  scales  in  the  middle  of  the  thorax  as  dark  as,  or  darker  than, 

those  along  the  side  n 

The  scales  in  the  middle  of  the  thorax  yellow,  those  along  the  broad 
sides  brown;  claws  of  the  hind  feet  simple  in  the  female. 

bracteatus  Coq. 

11.  Bristles  of  the  scutellum  yellow   12 

Bristles  of  the  scutellum  chiefly  black ;  upper  side  of  the  thorax  golden- 
yellow-scaled  and  devoid  of  stripes  of  darker  scales,  although  two 
darker  stripes  sometimes  appear  where  the  scales  are  very  sparse, 
each  stripe  being  scarcely  one-half  as  wide  as  the  yellow-scaled  space 
between  it  and  the  other  stripe pullatus  Coq. 

12.  In  the  middle  of  the  thorax  the  scales  are  wholly  yellow _ 13 

In  the  middle  of  the  thorax  is  a  pair  of  brown-scaled  stripes,  each 

stripe  being  slightly  wider  than  the  yellow-scaled  space  between  it 
and  the  other  stripe lazarensis  F.  &  Y. 

13.  Claspers  of  the  male  with  a  long,  stout  spine  near  the  base  of  the 

inner  side  impiger  Walk. 

Claspers  without  such  a  spine : abserrattis  Felt. 

14.  With  a  median  stripe  of  scales  on  the  thorax  of  a  different  color  from 

those  along  the  sides  T5 

Without  such  a  stripe ;  abdomen  black-scaled  and  with  the  front  angles 
of  some  of  the  segments  white-scaled;  claws  on  all  of  the  feet  of 
female  toothed.     (Middle  America) nubilus  Theob. 


ETIOLOGY 


95 


15.  Scales  m  the  middle  of  the  thorax,  at  least  on  its  anterior  half,  white, 

the    remainder    brown;    claws    on    all    of    the    feet    of    the    female 

toothed  !(5 

Scales  in  the  middle  of  the  thorax  black,  the  remainder  yeliow  or 
whitish    j5 

16.  Stripe  of  white  scales  in  the  middle  of  the  thorax  extending  entirely 

across  the  latter  Ty 

Stripe  of  white  scales  confined  to  the  anterior  two-thirds  of  the 
thorax    confirmatus  Arrib. 

17.  White-scaled   stripe  of  the   thorax   much  narrower   than   the  brown- 

scaled  portion  on  each  side  of  it serratus  Theob. 

White-scaled  stripe  wider  than  the  brown-scaled  portion  on  each 
side  of  it dupreei  Coq. 

18.  Upper  surface  of  the  thorax  white-scaled  toward  the  sides;  claws  on 

the  hind  feet  of  the  female  simple triseriatus  Say. 

Upper  surface  of  the  thorax  golden-yellow-scaled  toward  the  sides; 
claws  on  the  hind  feet  of  the  female  toothed aurifer  Coq. 

19.  Proboscis   blackish   and  with   a   white  band   near   the   middle;    white 

bands  of  the  feet  confined  to  the  bases  of  the  joints,  except  on  the 

hind  feet,  the  last  joint  of  which  is  sometimes  wholly  white 20 

Proboscis  blackish,  not  distinctly  banded  near  the  middle 22 

20.  Abdomen  black-scaled,  each  segment  with  a  basal  band  and  median 

longitudinal  stripe  of  yellowish  scales,  and  with  a  white-scaled  spot 

in  the  middle  of  each  side 21 

Abdomen  black-scaled,  each  segment  with  a  band  at  the  base  and  a 
spot  in  the  middle  of  each  side  white-scaled,  wing  scales  wholly 
black tczniorhynchus  Wied. 

21.  Wing  scales  mixed  black  and  yellowish;  light  colored  scales   of  the 

legs  yellow,  usually  a  whitish  band  in  the  middle  of  the  first  joint 

of  the  feet solicitans  Walk. 

Wing  scales  wholly  black;  light  colored  scales  of  the  legs  pure  white, 
first  joint  of  the  feet  never  with  a  light  colored  band  in  the  middle. 

mitchellce  Dyar. 

22.  Joints  of  the   fe^et  having  the  white  bands  situated  at  both   ends  of 

some  of  them," last  joint  of  the  hind  feet  white 23 

Joints  of  the  feet  having  the  white  bands  situated  at  the  bases  only 
of  some  of  them,  last  joint  of  the  hind  feet  black  except  sometimes 
its  extreme  base   28 

23.  Black  scales  mixed  with  white  ones  on  the  wings;  abdomen  whitish 

or  yellow-scaled  and  with  a  pair  of  black-scaled  spots  on  some  of 

the  segments  24 

Black  scales  only  on  the  wings,  abdomen  black-scaled,  sometimes  with 
aband  of  white  scales  at  the  bases  of  the  segments 25 

24.  Stripe  of  scales  in  the  middle  of  the  thorax  deep  golden  brown,  cover- 

ing more   than   one-fifth   of  the   width   of  the   thorax,   its   borders 

well  defined.     (Salt  water  species) lativittatus  Coq. 

Stripe  pale  brown,  covering  less  than  one-ninth  of  the  width  of  the 
thorax,  its  borders  not  strongly  marked,  usually  a  narrow  stripe  of 
brown  scales  on  each  side  of  it  separated  by  yellowish  white  scales 
(Fresh  water  species)   curriei  Coq. 

25.  Upper  side  of  the  thorax  light-yellow-scaled  and  with  a  broad  stripe 

of  black  scales  in  the  middle ;  palpi  wholly  black-scaled  in  both  sexes  ; 
abdomen  black-scaled  and  with  a  band  of  white  scales  at  the  base  of 

each  segment  atropalpus  Coq. 

Upper  side  of  the  thorax  not  marked  as  above;  palpi  with  whitish 
scales  at  the  apices  in  the  female  and  with  bands  of  them  in  the 
male   2g 

26.  Segments  of  the  abdomen  with  distinct  whitish  bands  at  their  bases ; 

scales  of  the  upper  side  of  the  thorax  brown  and  light  yellowish. 

varipalpus  Coq. 

Segments  of  the  abdomen  never  with  distinct  whitish  bands ;  scales  of 

the  upper  side  of  the  thorax  wholly  yellow 27 


96  THE   STUDY   OF  MALARIA 

27.  Hind  feet  almost  wholly  white-scaled nivitarsis  Coq. 

Hind  feet  largely  black-scaled canadensis  Theob. 

28.  Dorsum  of  the  abdomen  black-scaled  and  with  a  band  of  light-colored 

scales  at  the  base  of  each  segment 30 

Dorsum  of  the  abdomen  not  marked  as  above 29 

29.  Abdomen  wholly  light-yellow-scaled fletcheri   Coq. 

Abdomen  black-scaled  and  with  white  spots  on  the  sides ;  thorax  black- 
scaled  and  with  four  lines  of  yellow  scales.     (Middle  America.) 

quadrivittatus  Coq. 

30.  White  band  at  the  base  of  the  second  joint  of  the  hind  feet  covering 

at  least  one-third  of  the  length  of  the  joint;  claws  of  the  hind  feet 

toothed  in  the  female 32 

White  band  covering  less  than  one-fourth  of  the  length  of  the  second 
joint  of  the  hind  feet 31 

31.  Seventh  segment  of  the  abdomen  almost  wholly  yellow-scaled,  many 

yellow  scales  in  the  central  portion  of  the  preceding  segment;  claws 

of  the  hind  feet  of  the  female  simple cantator  Coq. 

Seventh  and  preceding  segment  chiefly  black-scaled;  claws  of  the  hind 
feet  of  the  female  toothed sylvestris  Theob. 

32.  Claspers  of  the  male  having,  near  the  base  of  the  inner  side,  a  large 

process  thickly  covered  with  hairs fitchii  Felt. 

Claspers  without  such  a  process. 

subcantans  Felt,  abfitchii  Felt,  vittata  Theob. 

(b)  List  of  the  Species  and  Synonyms 

abfitchii  Felt.  mitchellae  Dyar. 

siphonalis  Grossb.  nivitarsis  Coq. 

abserratus  F.  &  Y.  nubilus  Theob. 

atropalpus  Coq.  pretans  Grossb. 

aurifer  Coq.  pullatus  Coq. 

bimaculatus  Coq.  quadrivittatus  Coq. 

bracteatus  Coq.  serratus  Theob. 
cantator  Coq.  mathisi  Neveu-Lem. 

canadensis  Theob.  sollicitans  Walk, 

cinereoborealis  F.  &  Y.1  spenceri  Theob. 

trichurus  Dyar.  idahoensis  Theob. 

confirmatus  Arrib.  subcantans  Felt, 

curriei  Coq.  sylvestris  Theob.  _ 

dupreei  Coq.  tseniorhynchus  Wied. 
fitchii  F.  &  Y.  damnosus   Say. 

fletcheri  Coq.  triseriatus  Say. 
impiger  Walk.  nigra  Ludlow  (Finlaya). 

implacabilis    Walk.  trivittatus  Coq. 

knabi  Coq.  varipalpus  Coq. 
lativittatus  Coq.  sierrensis  Ludlow, 

lazarensis  F.  &  Y. 

(c)  Unrecognized  Species 

aestivalis  Dyar,  auroides  Felt,  excrucians  Walker,  hirsuteron  Theob., 
inconspicuus  Grossb.,  nemorosus  Meigen,  onondagensis  Felt,_  pallidohirta 
Grossb.,  portoricensis  Ludlow,  provocans  Walker,  punctor  Kirby,  reptans 
Meigen,  stimulans  Walker,  testaceus  van  der  Wulp,  and  tortilis  Theobald. 

xThe  writer's  copy  of  Science  containing  the  original  description  of  this 
species  was  received  September  2,  1904,  and  the  National  Museum  copy 
is  stamped  as  having  been  received  on  the  same  date.  The  writer's  copy 
of  the  Journal  of  the  New  York  Entomological  Society  which  contains 
the  original  description  of  trichurus  was  received  September  6,  1904;  the 
National  Museum  copy  and  that  of  the  U.  S.  Department  of  Agriculture 
are  stamped  with  the  same  date — September  6,  1904. 


ETIOLOGY  97 

Genus  GRABHAMIA  Theobald 

(Synonym:  Feltidia  Dyar) 

(a)  Table  of  the  Species 

i.  Feet  unicolorous  brown,  wing  scales  wholly  brown.     (West  Indies) . .  2 

Feet  brown  and  with  bands  of  white  scales  at  bases  of  some  of  the 

joints   3 

2.  With  an  ovate,  velvety-black  spot  above  the  insertion  of   each  wing; 

abdomen  black-scaled,  unmarked ocellatus  Theob. 

Without  such  a  spot;  abdomen  black-scaled  and  with  a  white-scaled 
spot  in  the  front  angles  of  the  posterior  segments. 

scholasticus  Theob. 

3.  Proboscis  black-scaled  and  with  a  light-colored  band  near  the  middle ; 

a  white  band  before  the  apex  of  each  hind  femur 4 

Proboscis  wholly  black;  abdomen  black-scaled  and  with  a  white  band 
at  the  bases  of  the  segments ;  no  white  band  before  the  apex  of  the 
hind  femora.     (West  Indies) imitator  Theob. 

4.  Wing  scales  black  and  whitish 5 

Wing  scales  wholly  black;   abdomen  black-scaled  and  with   a  narrow 

white,   usually   interrupted,   band   at   apex    of    each    segment.      (West 
Indies) con  finis  Arrib. 

5.  Last  vein  with  many  black  scales  on  the  basal  portion 6 

Last  vein  wholly  white-scaled  on  the  basal  two-thirds;  light  and  dark 

scales  of  the  wings  collected  into  spots,  costa  mixed  black  and  whitish 
scaled  and  with  a  long  whitish  spot  beyond  the  apex  of  the  auxiliary 
vein discolor  Coq. 

6.  Costa  and  veins  bearing  mixed  black  and  whitish  scales,  the  latter  not 

forming  distinct  spots 7 

Costa  black  and  whitish  scaled,  the  apical  half  with  four  long  spots  of 
whitish  scales  alternating  with  three  long  spots  of  black  ones. 

signipennis  Coq. 

7.  First  joint  of  the  hind  feet  light  colored  in  the  middle,  a  small  but 

distinct  black-scaled  spot  at  the  base  of  the  third  vein. 

jamaicensis  Theob. 

First  joint  of  the  hind  feet  black  in  the  middle,  no  distinct  black  spot  at 

the  base  of  the  third  vein pygmceus  Theob. 

(b)  List  of  the  Species  and  Synonyms 

confinis  Arrib.  ocellatus   Theob. 

discolor  Coq.  pygmaeus  Theob. 

imitator  Theob.  antiques  Giles, 

jamaicensis  Theob.  nanus  Coq. 
confinis   auct.    (all    references    to      scholasticus  Theob. 

its    occurrence    in    the    United      signipennis  Coq. 

States). 

(G.  deniedmannii  Ludlow  belongs  to  Lepidoplatys.) 

Genus  LUTZIA  Theobald 

Joints  of  the  feet  white  at  each  end,  abdomen  black-scaled  and  with  a 
large  apical  spot  of  white  scales  on  each  segment bigotii  Bell. 

Genus  CULICELLA  Felt 

(a)  Table  of  the  Species 

Feet  narrowly  white  at  the  bases  of  some  of  the  joints,  proboscis  without 
a  lighter  band  near  the  middle,  abdomen  black-scaled  and  with  a 
broad  band  of  yellow  scales  at  the  base  of  each  segment. .  .dyari  Coq. 

7 


98  THE   STUDY   OF   MALARIA 

(b)  List  of  the  Species  and  Synonymy 
dyari  Coq. 
brittoni  Felt. 

Genus  THEOBALDIA  Neveu-Lemaire 
(a)  Table  of  the  Species 

Front  side  of  the  hind  tibiae  chiefly  black-scaled,  the  apices  very  broadly 
whitish-scaled,  white  bands  of  the  feet  narrow,  the  dark  spots  on 
the  wings  large incidens  Thorn. 

Front  side  of  the  hind  tibiae  with  many  yellow  scales,  the  apices  narrowly 
and  indistinctly  whitish-scaled ;  the  dark  spots  on  the  wings  small. 

annulata  Schrank. 


(&)  List  of  the  Species  and  Synonyms 

k. 
s. 
variegata  Schrank. 


annulata  Schrank.  incidens  Thom. 

affinis  Stephens.  particeps  Adams 


Genus  CULISETA  Felt 
(a)  Table  of  the  Species 

Wing  scales  wholly  brown,  abdomen  brown-scaled  and  with  bands  of  light- 
colored  scales  at  the  bases  of  the  segments  in  both  sexes. 

absobrinus  Felt. 

Wing  scales  mixed  brown  and  yellowish  in  the  female,  abdomen  brown- 
scaled  and  with  bands  of  light-colored  scales  in  the  female,  un- 
handed in  the  male consobrinus  Desv. 

(&)  List  of  the  Species  and  Synonyms 

absobrinus  Felt.  inornatus  Will, 

consobrinus  Desv.  magnipennis  Felt. 

impatiens  Walk.  pinguis  Walk. 

Genus  CULEX  Linne 

(Synonyms:  Heteronycha  Arribalzaga,  Neoculex  Dyar) 

(a)  Table  of  the  Species 

1.  Feet  black,  both  ends  of  some  of  the  joints  white. 

janitor  Theob.,  pleuristriatus  Theob.,  secutor  Theob.,  tarsalis  Coq. 
Feet  uniformly  blackish 2 

2.  Light-colored  bands  of  scales  on  the  abdomen  situated  at  the  bases  of 

the  segments 3 

Light-colored  bands  located  at  the  apices  of  the  segments,  sometimes 
almost  wanting  territans  Walk. 

3.  Upper  side  of  the  thorax  dark-yellow-scaled,  and  usually  with  a  small 

round  dot  of  light-yellow  scales  on  each  side  of  the  center;  light- 
colored  bands  of  the  abdomen  broad  and  distinct ;  feet  with  very 
narrow,  indistinct  bands  of  light-colored  scales  at  the  sutures  of  the 

joints restuans   Theob. 

Upper  side  of  the  thorax  devoid  of  such  dots 4 

4.  Crossbands  of  light-colored  scales  indistinct  on  the  anterior  half  of  the 

abdomen,  almost  wanting  on  the  second  segment salinarius  Coq. 

Crossbands  distinct  5 

5.  Species  from  the  West  Indies palus  Theob. ;  similis  Theob. 

Species  almost  cosmopolitan pipiens  Linne. 


ETIOLOGY 


99 


(b)  List  of  the  Species  and  Synonyms 

janitor  Theob.  salinarius  Coq. 

palus  Theob.  nigritulus  auct.   (North  American 

pipiens  Linne.  references). 

boscii  Desv.  secutor  Theob. 

cubensis  Bigot.  similis  Theob. 

fatigans  auct.1    (North  American      tarsalis  Coq. 

references).  affinis  Adams  (not  of  Stephens). 

ferruginosus  Wied.     {Anopheles.)  kelloggii  Theob. 

pungens  Wied.  peus  Speiser. 

quinquefasciatus  Say.  willistoni  Giles, 

pleuristriatus  Theob.  territans  Walk, 

restuans  Theob.  apicalis  Adams. 

(c)  Unrecognized  Species 

flavipes  Macquart,  biocellatus  Theobald,  inflictus  Theob.,  micro squamosus 
Theob.,  nigripalpus  Theob.,  and  saxatilis  Grossbeck. 
(C.  penafieli  Williston  has  never  been  described.) 

Genus  MELANOCONION  Theobald 

1.  Hind  and  other  feet  wholly  black 2 

Hind  feet  white-scaled  on  the  broad  base  of  the  fourth  joint;  abdomen 

black-scaled,  a  row  of  violet-scaled  spots  along  the  sides.      (Middle 
America)    urichii  Coq. 

2.  Thorax  on  the  anterior  half  golden-yellow-scaled  and  with  a  pair  of 

black-scaled  spots,  the  posterior  half  black-scaled  and  with  two  stripes 

of  yellow  scales.      (Middle  America) spissipes  Theob. 

Thorax  wholly  golden-brown-scaled 3 

3.  Abdomen  with  bands  of  yellowish  scales  at  the  bases  of  the  segments. 

(Middle  America)   humilis  Theob. 

Abdomen  unhanded 4 

4.  Front  angles  of  the  segments  of  the  abdomen  yellowish-scaled. 

atratus  Theob. 
Front  angles  and  whole  of  the  abdominal  segments  black-scaled. 

indecorabilis  Theob.,  melanurus  Coq. 

Genus  TINOLESTES  Coquillett 

Feet  unicolorous  black ;  scales  of  the  upper  side  of  the  body  black  and 
with  light-colored  ones  in  the  front  angles  of  some  of  the  segments 
of  the  abdomen latisquama  Coq. 

Genus  MICRAEDES  Coquillett 

Proboscis  and  feet  unicolorous  black ;  scales  of  the  abdomen  purple-black 
and  with  light-colored  ones  in  the  front  angles  of  some  of  the 
segments  bisulcatus  Coq. 

Genus  ISOSTOMYIA  Coquillett 

Proboscis,  feet,  and  abdomen  wholly  black-scaled pcrturbans  Will. 

(Aedes  nigricorpus  Theobald  may  also  belong  to  this  genus.) 

'In  response  to  my  request,  Major  A.  Alcock,  superintendent  of  the 
natural  history  section  of  the  Indian  Museum  at  Calcutta,  India,  sent  me 
specimens  of  this  species  in  all  the  stages.  The  larvae  have  been  examined 
by  Dr.  H.  G.  Dyar  and  Mr.  F.  Knab,  who  report  having  discovered  differ- 
ences between  them  and  the  corresponding  stage  of  the  North  American 
specimens  of  pipiens. 


IOO  THE   STUDY   OF   MALARIA 

Genus  COQUILLETTIDIA  Dyar 

(a)  Table  of  the  Species 

1.  Scales  of  the  wings  mixed  black  and  light  colored,  those  of  the  costa 

not  forming  distinct  spots;  scales  of  the  feet  black  and  with  white 

ones  at  the  bases  of  some  of  the  joints 2 

Scales  of  the  wings  wholly  black.     (Middle  America) 3 

2.  Abdomen  black-scaled  and  with  a  white  band  at  the  base  of  each  seg- 

ment; hind  tibiae  with  a  broad  light-colored  band  before  the  apex. 

perturbans  Walk. 

Abdomen  golden-yellow-scaled  and  with  several  black  scales  on  the  first 

three  segments;  hind  tibiae  devoid  of  a  distinct  light-colored  band. 

(Middle  America)    flaveolus  Coq. 

3.  Feet  black-scaled  and  with  white  bands  at  the  sutures  of  some  of  the 

joints,   femora  with  a  whitish  spot  or  band  at  a  point  near  three- 
fourths  of  their  length 4 

Feet  wholly  black  except  at  the  base  of  the  first  joint,  femora  devoid 
of  a  distinct  white  mark  near  three-fourths  of  their  length;  abdomen 
black-scaled  and  with  a  white  band  or  median  spot  at  the  base  of  each 
of  the  last  four  segments  and  a  white  spot  in  the  front  angles  of 
each  segment _ palliatus  Coq. 

4.  Scales  on  the  upper  side  of  the  abdomen  black  and  with  spots  of  white 

ones  along  the  sides 5 

Scales  on  the  abdomen  wholly  black,  on  the  thorax  wholly  brown. 

arribalzagce  Theob. 

5.  White  spots  on  the  sides  of  the  abdomen  situated  in  the  front  angles 

of  the  segments;   scales  in  the  middle  of  the  thorax  yellow,  those 

toward  the  sides  chiefly  black nigricans  Coq. 

White  spots  on  the  sides  of  the  abdomen  situated  near  the  middle  of 
the  segments ;  scales  of  the  thorax  brown  and  with  several  lines  of 
light  yellow  ones fasciolatus  Arrib. 

(b)  Unrecognized  Species 

niger  Giles,  described  from  Antigua,  West  Indies. 

richardi  Ficalbi,  a  European  species  reported  from  Canada  by  Theobald. 

(c)  Species  Wrongly  Referred  to  this  Genus 

antique?  Giles  and  confinis  Arribalzaga  belong  to  Grabhamia;  fulvus 
Wiedemann  belongs  to  Psorophora;  sierrensis  Ludlow  belongs  to  Ochlero- 
tatus. 

Genus  T/ENIORRHYNCHUS  Arribalzaga 

(Synonyms  :  Mansonia,  Panoplites  Theobald) 

(a)  Table  of  the  Species 

Third  joint  of  the  feet  black-scaled,  the  base  narrowly  white-scaled,  scales 
of  the  tibiae  not  forming  distinct  spots  or  bands titillans  Walk. 

Third  joint  of  the  hind  feet  wholly  white-scaled,  black  and  yellowish  scales 
of  the  tibiae  collected  into  distinct  bands  and  spots fascipes  Coq. 

(b)  List  of  the  Species  and  Synonymy 

fascipes  Coq.  titillans  Walk. 

tceniorhynchus     Arrib.      (not     of 
Wiedemann). 

Genus  AEDEOMYIA  Theobald 

Proboscis  with  a  white  ring  near  the  middle;  joints  of  the  feet  white  at 
at  their  bases ;  scales  of  the  wings  brown,  yellow,  and  white. 

squamipennis  Arrib. 


ETIOLOGY  IOI 

Genus  ILEMAGOGUS  Williston 

(a)  Table  of  the  Species 

Scales  of  the  abdomen  bluish  and  with  a  row  of  silvery  spots  along  each 
side,  sometimes  a  small  median  spot  of  white  scales  on  some  of  the 
segments    cyaneus  Fab. 

(b)  List  of  the  Species  and  Synonymy 

cyaneus  Fab. 

splendens  Will. 

(The  following  two  species  were  originally  described  under  Hcemago- 
gus.) 

Genus  CACOMYIA,  new  genus 

Abdomen  having  white  scales  in  the  middle  of  the  last  two  segments  only. 

albomaculatus  Theob. 
Abdomen  having  white  scales  in  the  middle  of  some  of  the  other  seg- 
ments  equinus  Theob. 

Genus  GYMNOMETOPA  Coquillett 

i.  Upper  side  of  the  thorax  brown-scaled  and  with  six  narrow  lines  of 
pale  yellow  scales  extending  the  entire  length  of  the  thorax ;  last  two 

joints  of  the  hind  feet  black sexlmeata  Theob. 

Upper  side  of  the  thorax  not  marked  like  this 2 

2.  Last  two  joints  of  the  hind  feet  and  all  the  tibiae  black 3 

Last  two  joints  of  the  hind  feet  chiefly  white;  a  spot  or  band  of  white 

scales  on  the  base  of  at  least  the  first  two  joints  on  all  of  the  feet; 
tibiae  with  a  silvery  mark  at  a  point  about  one-fourth  of  their 
length  mediovittata  Coq. 

3.  With  a  dot  of  silvery  scales  in  the  middle  of  the   front  end  of  the 

thorax;  first  two  joints  of  the  front  feet  white-'scaled  at  their  bases. 

albonotata  Coq. 
Without  such  a  dot;  front  feet  wholly  black-scaled busckii  Coq. 

Genus  HOWARDINA  Theobald 

Feet  black-scaled,  the  base  of  the  first  three  joints  of  the  hind  ones  white- 
scaled;  upper  side  of  the  thorax  white-scaled  along  the  sides,  the 
median  portion  black-scaled  and  with  four  narrow  lines  of  pale  yellow 
scales,  the  two  middle  lines  united  into  a  single  line  posteriorly,  the 
outer  two  lines  situated  on  the  posterior  half  of  the  thorax. 

walkeri  Theob. 

Genus  PNEUMACULEX  Dyar 

Thorax  on  the  upper  side  velvety-brown-scaled  and  with  six  narrow  lines 
of  silvery  scales signifer  Coq. 

5.    Subfamily  DEINOCERITIN^E  Mitchell 

Genus  DEINOCERITES  Theobald 

(Synonym:  Brackiomyia  Theobald) 

(a)  Table  of  the  Species 

Proboscis  and  feet  unicolorous  blackish ;  scales  of  the  upper  side  of  the 
body  also  blackish cancer  Theob. 

(b)  List  of  the  Species  and  Synonymy 

cancer  Theob. 
magna  Theob. 


102  THE    STUDY   OF   MALARIA 

6.    Subfamily  URANOT^ENIIN^E  Lahille 

Genus  URANOT^NIA  Arribalzaga 

(a)  Table  of  the  Species 

i.  Thorax  with  a  median  line  of  bluish  scales;  feet  wholly  black 2 

Thorax  without  a  median  line;  hind  feet  white  on  at  least  the  last  two 
joints  and  broad  apex  of  the  third 3 

2.  Bluish  median  line  of  the  thorax  prolonged  to  the  scutellum. 

sapphirina  O.  S. 
Bluish  line  obliterated  before  reaching  the  scutellum socialis  Theob. 

3.  Scutellum  with  blue  scales ;  a  patch  of  blue  scales  on  the  thorax  a  con- 

siderable distance  in  front  of  the  scutellum ;  feet  white  at  the  sutures 

of  many  of  the  joints.     (Middle  America) geometrica  Theob. 

Scutellum  without  blue  scales ;  no  patch  of  blue  scales^  on  the  thorax 
in  front  of  it ;  feet  wholly  black  except  the  last  two  joints  and  apex 
of  the  third  in  the  hind  ones lowii  Theob. 

(b)  Unrecognized  Species 

apicalis  Theobald  and  pulcherrima  Arribalzaga.    Both  of  these  have  been 
reported  from  the  West  Indies. 

7.    Subfamily  TRICHOPROSOPONINiE  Theobald 
(Synonyms  :  Hyloconopin<z  Lutz,  DendromyincB  Lutz,  Sabettina  Blanchard) 

Table  of  the  Genera 

1.  Male  palpi  at  least  one-half  as  long  as  the  proboscis;   clypeus  hairy. 

(Middle  America)   . . .  Trichoprosopon 

Male  palpi  less  than  one-fourth  as  long  as  the  probiscis ;  clypeus  bare..  2 

2.  Veins  of  the  wings  having  the  outstanding  scales  narrow  and  nearly 

linear;   hind  cross-vein  situated  at  least  its   own   length  before  the 

small  cross-vein  ;  legs  never  fringed  with  scales Wyeomyia 

Veins  having  many  rather  broad  outstanding  scales.  (Middle  Amer- 
ica)       3 

3.  Hind  cross-vein  slightly  before,  opposite,  or  beyond  the   small  cross- 

vein,  each  foot  bearing  two  claws 7 

Hind  cross-vein  at  least  twice  its  own  length  before  the  small  cross- 
vein  ;  legs  never  fringed  with  scales < 4 

4.  With  two  claws  on  each  hind  foot;  no  scales  on  the  posterior  end  of 

the  thorax  below  the  scutellum ; 5 

With  only  one  claw  on  each  hind  foot  in  both  sexes;  posterior  end  of 
the  thorax  below  the  scutellum  bearing  several  broad  scales  in  addi- 
tion to  the  bristles 6 

5.  Proboscis  shorter  than  the  body;  thickened  before  its  apex.  .Dendromyia 
Proboscis  longer  than  the  body,  not  thickened  toward  its  apex. 

Phoniomyia 

6.  Male  proboscis  strongly  curved  in  the  outer  half  and  with  a  cluster  of 

scales  at  each  end  of  the  curved  portion Limatus 

7.  Legs  not  fringed Sabethoides 

Legs  fringed  in  places  with  outstanding  scales  in  both  sexes Sabethes 

Genus  TRICHOPROSOPON  Theobald 

(Synonym:  Joblotia  Blanchard) 

Feet  wholly  black lunata  Theob. 

Feet  black,  the  last  four  joints  of  the  middle  feet  and  the  last  two  of  the 
hind  ones  white nivipes  Theob. 


ETIOLOGY 


Genus  WYEOMYIA  Theobald 


103 


Proboscis  and  upper  side  of  the  abdomen  wholly  black -scaled. 

grayi  Theob.,  pertinans  Will.,  smithii  Coq. 

Genus  DENDROMYIA  Theobald 

Abdomen  wholly  black-scaled  on  the  upper  side ;  humeri  black-scaled ;  first 
joint  of  the  hind  feet  shorter  than  their  tibiae. .  .luteoventralis  Theob. 

Genus  PHONIOMYIA  Theobald 
(a)  Table  of  the  Species 
Abdomen  black-scaled,  the  front  angles  of  the  segments  white-scaled. 

longirostris  Theob. 

(&)  List  of  the  Species  and  Synonymy 

longirostris  Theob. 
trinidadensis  Theob. 

Genus  LIMATUS  Theobald 

(Synonym:  Simondella  Laveran) 

Thorax  golden-yellow-scaled,  a  median,  Y-shaped  spot,  with  the  prongs 
nearest  the  head,  and  a  large  spot  above  each  wing  violet-blue- 
scaled  durhamii  Theob. 

Genus  SABETHOIDES  Theobald 

Abdomen  black-scaled,  the  under  side  and  front  angles  of  the  segments 
whitish-scaled,  the  white-scaled  front  angles  prolonged  so  as  to 
form  a  crossband  which  is  interrupted  except  sometimes  on  the  last 
three  segments confusus  Theob. 

Abdomen  black-scaled,  the  under  side  whitish-scaled,  and  encroaching  on 
the  sides  of  the  dorsum,  the  border  of  the  two  colors  strongly  undu- 
lating   undosus  Coq. 

Genus  SABETHES  Desvoidy 
(o)  Table  of  the  Species 

1.  Front  and  hind  legs  not  fringed 2 

Front  and  other  legs  fringed  in  places  with  outstanding  scales ;  middle 

legs  white-scaled  before  and  beyond  the  fringed  portion;  the  broad 
apices  of  the  hind  feet  chiefly  white-scaled longipes  Fab. 

2.  Legs  black-scaled,  the  apical  part  of  the  fringe  on  the  middle  legs  white. 

t            u  11     1  1     1         t  j  nitidus  Theob. 

Legs  wholly  black-scaled locuples  Desv. 

(b)  List  of  the  Species  and  Synonymy 
locuples  Desv.  longipes  Fab. 

remipes  Wied.  nitidus  Theob. 

The  hatching  of  the  first  brood  of  anophelines  bears  an  inti- 
mate relation  to  the  seasonal  occurrences  of  malaria.  The 
seasonal  variations  of  different  species  are  probably  dependent 
upon  the  presence  or  absence  of  breeding  pools  suitable  to 
particular  species.  Temperature  also  exerts  an  influence,  the 
hibernating  females  of  some  species  leaving  winter  quarters 


104  THE   STUDY   OF   MALARIA 

earlier  than  others,  and  hibernating  larvae  mature  at  different 
temperatures. 

While  the  anophelines  are  mosquitoes  of  low  altitudes,  they 
may  be  found  at  considerable  elevations.  Thus  in  the  Alps 
they  are  found  at  an  altitude  of  1,145  metres;  in  the  Ap- 
penines  at  1,283  metres;  in  Java  at  1,000  metres;  at  Harrar 
at  2,000  metres;  in  Africa  at  1,900  metres,  and  in  the  high 
plateaus  of  Mexico  at  2,000  metres.115 

It  is  the  rule  among  mosquitoes  that  only  the  females  are 
blood  suckers,  hence  it  is  this  sex  alone  that  is  concerned  in 
the  propagation  of  malaria.  The  female  insects  suck  not  only 
the  blood  of  man,  but  of  other  mammals,  birds,  occasionally 
of  cold-blooded  animals,  and  even  other  insects.  Blood  is 
necessary  for  both  the  procreation  of  mosquitoes  and  the  devel- 
opment of  the  sexual  cycle  of  the  malarial  organism.  While 
both  sexes  have  the  blood-sucking  apparatus,  the  puncturing 
portion  of  the  proboscis  of  the  male  is  much  weaker  than  that 
of  the  female. 

There  are  a  few  exceptions  to  the  rule  that  males  do  not 
bite.  While  males  do  not  infrequently  light  upon  the  skin  and 
probe  around  with  the  proboscis,  they  usually  fly  away  without 
partaking  of  blood.  But  the  male  Stegomyia  fas  data  has  been 
known  to  bite.  Doctor  Stilesm4  is  said  to  have  been  bitten  by 
a  male  Culex  nemoralis,  and  the  male  of  Culex  elegans  is  said 
by  Sambon1,21  to  be  quite  as  bloodthirsty  as  the  female.  The 
habitual  diet  of  male  mosquitoes,  however,  is  vegetarian.  They 
are  very  fond  of  fruits,  as  bananas,  dates,  pears,  apples,  melons, 
and  of  the  nectar  of  flowers,  wine,  and  beer.  In  captivity  mos- 
quitoes may  be  kept  alive  for  some  days  upon  a  diet  merely 
of  sweetened  water. 

Anopheline  mosquitoes  rarely  suck  blood  except  during  the 
night.  After  feeding  they  usually  retire  to  remote  and  dark 
corners  or  to  breeding  places  to  oviposit.  Persons  may  be 
bitten  during  sleep  without  being  disturbed,  since  these  insects 
are  not  noisy  and  their  bite  is  not  particularly  painful.  During 
the  day  their  reserved  habits  make  them  difficult  of  detection. 
They  will  ordinarily  feed  in  a  few  hours  after  hatching;  in 
captivity,  however,  it  may  be  difficult  to  induce  them  to  feed 


ETIOLOGY  105 

upon  blood.  The  meal  is  repeated,  as  a  rule,  once  every  day 
or  every  few  days.  Blood  is  essential  for  the  maturation  of 
fertile  ova,  one  feeding  being  sufficient  for  one  oviposition. 
The  act  of  biting  (Fig.  40)  has  been  described  as  follows: 
"When  the  female  anopheles  bites  the  proboscis  is  pointed 
downwards  and  the  labellse  are  pressed  against  the  skin  of  the 
victim.  The  labrum,  the  hypopharynx,  the  mandibles,  and  the 
maxillae  are  pressed  together  into  one  solid  boring  instrument, 
like  the  parts  of  a  trocar.  Their  common  tip  is  forced  down  at 
the  angle  between  the  spread  labellse,  which  serve  to  hold  and 
direct  these  clustered  parts.  Whilst  the  piercing  organs  pass 
into  the  tissues  the  labium  bends  backwards  at  about  a  third 
from  its  base,  and  its  angle,  pointing  towards  the  breast  of  the 
insect,  becomes  more  and  more  acute  with  the  deepening  of  the 


t 

Fig.  40. — A  female  mosquito  in  the  act  of  biting. 

mouth  parts.  The  palpi,  which  usually  lie  parallel  with  the 
proboscis,  are  raised  and  diverged  during  puncture."1121 

The  buzzing  note  of  the  mosquito  is  produced  by  the  vibra- 
tions of  the  chitinous  shreds  within  the  large  tracheae  and  not 
by  the  wings,  as  commonly  supposed.  As  Howard122  states, 
there  is  quite  a  difference  between  the  note  of  Anopheles 
maculipennis  and  that  of  the  common  species  of  culex,  the  note 
of  the  latter  being  high  in  pitch,  that  of  the  former  being  sev- 
eral tones  lower. 

A  point  of  great  practical  interest  is  the  length  of  flight  of 
the  mosquito  and  the  extent  to  which  it  may  be  borne  by  the 
wind.  It  is  a  general  rule  that  mosquitoes  do  not  migrate  far 
from  their  native  pools  or  from  dwellings  where  nourishment 
may  be  obtained. 

It  is  very  unusual  for  anophelines  to  fly  farther  than  a  few 
hundred  yards,  and  half  a  mile  may  be  regarded  as  the  maxi- 


106  THE   STUDY   OF   MALARIA 

mum  limit  of  flight.  They  are  poorer  flyers  than  most  other 
species.  For  this  reason  they  are  less  often  borne  by  the  wind, 
since  they  seek  shelter  when  a  breeze  arises.  While  the  wind 
is  not  so  generally  a  vehicle  for  the  dissemination  of  mosquitoes 
as  commonly  believed,  certain  species,  especially  of  salt  water 
breeders,  are  borne  by  the  wind  for  several  miles.  The  greater 
prevalence  of  mosquitoes  in  dwellings  after  a  wind  may  often 
be  due  to  their  retiring  thither  for  protection.  Mosquitoes  may 
be  carried  in  wagons  loaded  with  straw,  hay,  or  fruit,  and 
upon  railroad  cars.  Many  localities  formerly  free  from  the 
pests  date  their  affliction  with  mosquitoes  from  the  introduction 
of  railroads.  Vessels  may  not  only  transport  the  insects  for 
great  distances,  but  may  even  afford  breeding  places. 

The  preference  of  anophelines  for  certain  colors  has  been 
demonstrated  by  Nuttall.123.  Boxes  lined  with  cloth  of  differ- 
ent colors  were  placed  where  the  mosquitoes  were  plentiful, 
and  on  seventeen  days  the  number  on  each  box  was  counted, 
with  the  following  result: 

Color  of  bo-c  Number  of  Anopheles  malculipennis  counted 

in  each  box  during  seventeen  days. 

Navy  blue 108 

Dark  red  90 

Brown,  reddish 81 

Black 49 

Scarlet  59 

Slate  gray  31 

Dark  green  (olive)    24 

Violet   18 

Leaf  green  17 

Blue   14 

Pearl  gray 9 

Pale  green    4 

Light  blue  3 

Ochre    2 

White   2 

Orange  1 

Yellow ._. 

512 

Galli-Valerio  and  De  Jongh124  counted  119  anophelines  rest- 
ing upon  dark  colors  and  33  upon  bright  colors,  and  349  culex 
upon  dark  colors  and  120  upon  bright. 

Mosquitoes  are  fond  of  the  odor  of  leather  and  are  usually 
plentiful  upon  harness  hanging  in  stables.  They  are  said  to 
prefer  the  odor  of  the  negro  to  that  of  the  white  man. 


ETIOLOGY 


107 


Anophelines,  like  other  malefactors,  prefer  darkness  rather 
than  light,  and  seek  the  sequestered  nooks  during  the  day. 

A  meal  of  blood  is  a  prerequisite  to  fertilization.  Females 
confined  with  males,  then  isolated  and  fed,  do  not  deposit 
fertile  eggs,  but  must  be  fed  first.  A  single  fertilization  is 
sufficient  for  several  batches  of  eggs.  These  are  usually  de- 
posited between  dusk  and  dawn.  Still  water  is  necessary,  since 
the  female  may  be  drowned  if  the  surface  is  agitated.  The 
female  sits  upon  the  water  or  upon  the  edge  of  floating  leaves 
or  debris.  The  ova  of  anophelines  are  deposited  upon  the 
water  in  clumps,  but  soon  separate  and  lie  horizontally.  A 
batch  of  ova  usually  numbers  from  100  to  150.  Pressat125 
has  calculated,  on  a  basis  of  150  ova  for  each  female,  hatching 
50  per  cent,  females,  that  a  single  female  in  one  season  pro- 
duces about  five  billion  mosquitoes. 

Parthenogenesis  has  occasionally  been  observed  in  mosqui- 
toes. Kellogg114  reared  a  female  mosquito  from  the  pupa 
which  almost  immediately  deposited  eggs;  she  had  not  been 
fertilized.  Larvae  developed  from  the  ova  and  nearly  reached 
full  growth  before  dying.  Unfertilized  female  Stegomyia 
fasciata  and  Culex  pipiens  have  also  been  known  to  deposit 
ova,  which,  however,  were  not  fertile. 

It  is  impossible  to  determine  the  length  of  life  of  mosquitoes 
in  nature,  though  even  in  captivity  they  have  been  kept  for 
weeks.  Anophelines  have  been  kept  alive  five  days  with- 
out food  or  water,  and  for  about  two  months  fed  upon 
bananas.  The  males  are  not  so  long  lived  as  the  females. 
Mitchell126  has  kept  Stegomyia  fasciata  sixty-one  days.  It  is 
well  known  that  mosquitoes  survive  long  droughts,  as  well  as 
hibernate. 

Stephens  and  Christophers118  say  there  is  evidence  that  the 
ova  can  survive  for  some  months  in  moist  earth  and  exposed 
to  frost.  Eysell1127  and  Galli-Valerio  and  De  Jongh12*  state 
that  the  ova  of  most  species  of  mosquitoes  of  the  northern 
temperate  and  frigid  zones  may  hibernate. 

Mosquitoes  hibernate  in  the  larval  stage  also.  Smith114 
found,  in  New  Jersey,  larvae  of  Culex  pungens  in  ice  contained 
in  pitcher  plants,  and  believes  that  larval  hibernation  must  be 


108  THE   STUDY  OF  MALARIA 

extremely  common.  Mitchell126  found  anopheles  larvae  in 
tanks  and  barrels  in  the  Botanical  Gardens  of  Washington, 
D.  C,  during  winter,  and  Woldert12S  found  these  larvae  in 
December  at  Tyler,  Texas. 

Mitchell126  believes  it  probable  that  mosquitoes  do  not  hiber- 
nate in  the  pupal  stage,  though  Galli-Valerio  and  De  Jongh124 
maintain  the  opposite  opinion. 

It  is  chiefly  in  the  winged  stage  that  mosquitoes  hibernate. 
In  the  late  fall  the  males  die,  the  fecundated  females  seeking 
shelter  in  dwellings,  cellars,  stable,  barns,  cisterns,  hollow  trees, 
or  under  bridges.  Annett  and  Dutton129  thus  describe  the 
hibernation  of  Anopheles  maciilipennis  in  England : 

i.  The  attitude  is  peculiar,  the  insect  lying  quite  flat  upon 
the  surface  with  its  legs  spread  out.  In  this  position  the  under 
surface  of  the  thorax  touches,  or  nearly  touches,  the  wall. 

2.  Only  females  are  found,  and  these  are  always  fertilized, 
and  have  the  spermatheca  filled  with  spermatozoa. 

3.  The  insects  are  difficult  to  arouse  and  very  sluggish  in 
any  movements  they  make. 

4.  They  do  not  feed  unless  the  temperature  is  raised.  If 
kept  at  a  low  temperature  (provided  the  air  is  moist)  they 
remain  for  weeks  without  feeding. 

5.  If  aroused  by  raising  the  temperature  they  feed  readily 
and  the  ovaries  rapidly  develop.  Eggs  are  laid,  and  in  most 
cases  the  female  dies  after  their  deposition. 

Study  of  Mosquitoes. — To  obtain  adult  mosquitoes  they 
may  be  either  captured  or  bred  from  larvae.  Mosquitoes  are 
best  captured  by  placing  very  carefully  the  mouth  of  a  test 
tube  or  bottle  over  the  insects  while  resting.  They  are  killed 
preferably  by  the  cyanide  bottle,  by  chloroform,  or  by  tobacco 
smoke.  The  cyanide  bottle  is  prepared  by  placing  in  the  bot- 
tom of  a  wide-mouthed  bottle  a  number  of  small  pieces  of 
potassium  cyanide  and  covering  with  liquid  plaster  of  Paris. 
When  the  plaster  has  hardened  the  bottle  is  ready  for  use,  and 
should  then  be  kept  tightly  corked,  as  the  fumes  are  poisonous. 
Mosquitoes  should  not  be  killed  immediately  after  hatching, 
as  the  exoskeleton  is  then  soft  and  marked  shrivelling  occurs. 
A  net  should  not  be  used  for  capturing  adult  mosquitoes,  for 


ETIOLOGY  IO9 

the   delicate  scales   are  thereby   worn  off   and  the   specimen 
spoiled. 

Mosquitoes  should  be  mounted  as  soon  as  killed,  since  the 
legs  soon  lose  their  pliability  and  are  apt  to  be  broken  off. 
The  materials  needed  for  mounting  are  fine  entomological 
pins,  No.  00 ;  ordinary  black  or  mourning  pins,  and  cardboard 
slips.  These  latter  may  be  cut  oblong,  one-half  by  1  inch,  or 
circular,  using  a  16  or  20-gauge  wad-cutter.  One  of  the  fine 
pins  is  run  for  two-thirds  of  its  length  through  one  of  the 
cardboard  slips.  The  mosquito,  lying  upon  its  back  upon  a 
piece  of  cork,  is  transfixed  by  the  point  of  this  pin  through 
the  center  of  origin  of  the  legs.  One  of  the  larger  pins  is  now 
run  through  the  cardboard  in  an  opposite  direction,  and  when 
stuck  into  the  cork  lining  of  the  cabinet  serves  as  a  support. 


Fig.  41. — A  pinned  specimen. 


Naphthaline  or  camphor  should  be  placed  in  the  cabinet  to 
exclude  mites. 

Parts  of  mosquitoes,  the  wings,  legs,  antennae,  scales,  etc., 
may  be  mounted  upon  slides.  A  ring  of  varnish  should  be 
made  upon  a  slide  and  the  object  placed  in  the  center  of  this 
ring,  the  cover-glass  pressed  down  gently  and  its  edge  ringed, 
preferably  with  Damar. 

Ova,  larvae,  and  pupae  may  be  mounted  in  concave  slides  or 
upon  slides  having  a  cell  made  by  ringing  with  varnish.  In 
this  cell  the  object  is  mounted  with  Farrant's  medium  or  with 
10  per  cent,  solution  of  formalin,  and  the  edge  of  the  cover- 
glass  ringed. 

In  order  to  catch  larvae  the  only  implements  required  are 
a  white  enamelled  dipper,  a  spoon,  and  a  container  for  the 
wrigglers  when  captured.  To  "breed  out"  larvae  they  should 
be  placed  in  wide-mouthed  jars  half  filled  with  water  and  a 


110  THE   STUDY   OF   MALARIA 

layer  of  sand  in  the  bottom,  and  covered  with  gauze  held  in 
place  by  means  of  a  rubber  band.  The  larvse  in  each  jar 
should  be  near  the  same  size,  otherwise  the  larger  will  devour 
the  smaller  ones,  and  they  should  not  be  too  numerous.  A 
few  grains  of  dry  rice  should  be  dropped  in  for  food. 

Adults  also  should  be  kept  in  such  jars,  which  should,  how- 
ever, contain  only  a  small  quantity  of  water,  upon  which 
should  float  a  thin  sheet  of  cork,  and  each  jar  should  contain 
a  slanting  strip  upon  which  the  insects  may  rest.  A  bent 
hairpin  makes  a  good  hook  upon  which  to  suspend  a  piece  of 
fruit  from  the  edge  of  the  jar. 

In  order  to  infect  mosquitoes  with  malaria  they  must,  of 
course,  be  fed  upon  blood  containing  parasites.  They  may 
be  fed  by  holding  the  moistened  forearm  against  the  gauze 
covering  of  the  jar  or  they  may  be  placed  in  cages  covered 


Fig.  42. — Stomach  of  infected  mosquito. 

with  wire  netting,  one  end  of  which  has  an  opening  protected 
by  a  sleeve  through  which  the  arm  may  be  introduced.  The 
mosquitoes  should  be  fed  in  twenty-four  to  forty-eight  hours 
after  hatching  and  thereafter  every  day  for  several  days. 

In  investigating  the  mosquito  cycle  of  the  parasite  of  mala- 
ria the  sexual  forms  must  be  sought  for  in  the  midgut  or 
stomach,  and  the  sporozoits  in  the  salivary  glands. 

In  the  dissection  of  the  midgut  proceed  as  follows : 

Do  not  dissect  the  mosquito  until  the  blood  from  the  last 
feeding  is  digested,  which  may  be  ascertained  by  the  disap- 
pearance of  the  dark  color  on  the  lower  surface  of  the  abdo- 
men. 

Kill  the  mosquito  by  means  of  cyanide  fumes,  chloroform, 
ether,  or  tobacco  smoke. 

Pull  off  the  wings  and  legs  and  remove  the  scales  with  a 
small  camel's-hair  brush. 


PLATE  I 


T*    r.  "py  ^t  W   1*« 


^r*^»  ^*P  ^ 


A  miniature  mosquito  farm. 


ETIOLOGY 


III 


Place,  with  the  ventral  aspect  up,  in  a  drop  of  normal  salt 
solution  upon  a  glass  slide. 

Transfix  the  center  of  the  thorax  with  a  dissecting-  needle. 

Flatten  the  abdomen  by  gentle  pressure  of  the  other  needle, 
and  nick  the  intersegmental  membrane  on  each  side  between 
the  second  and  third  last  segments. 


Fig.  43. — Midgut,  Malpighian  tubules,  and  ovaries  of  the  mosquito. 

With  the  needle  upon  the  last  segment,  pull  gently  until  the 
segments  separate  and  the  viscera  are  drawn  out. 

Separate  the  stomach  from  the  esophagus  in  front  and  from 
the  hind-gut  and  Malpighian  tubules  behind,  and  remove  these 
organs. 

Add  more  salt  solution  if  necessary  and  apply  a  cover-glass 

The  salivary  glands  (Fig.  44)  lie  immediately  above  the 
origin  of  the  first  pair  of  legs.    One  method  of  removing  them 


Fig.  44. — Dissection  of  the  salivary  glands  (after  Daniels). 

is  to  transfix  the  posterior  portion  of  the  thorax  with  one 
needle  and  with  the  other  pull  off  the  head,  when  the  salivary 
glands  and  a  tag  of  the  esophagus  are  dragged  out.  Another 
method  is,  after  removing  the  wings  and  legs,  to  cut  off  the 
head  and  to  make  an  incision  parallel  to  the  anterior  border  of 
the  thorax  and  on  a  level  with  the  middle  pair  of  legs.  The 
glands  are  teased  out  of  this  segment  after  first  cutting  the 
exoskeleton  in  several  places.  They  are  recognized  as  trans- 
lucent glistening  bodies. 


112  THE   STUDY   OF   MALARIA 

THE  PARASITES  OF  MALARIA 
Zoological  Relations. — The  parasites  of  malaria  belong  to 
the  animal  kingdom,  to  the  division  of  protozoa,  to  the  class 
of  sporozoa,  and  to  the  order  of  hemosporidia.  The  hemo- 
cytozoa  are  not  peculiar  to  man,  but  are  found  in  other  classes 
of  vertebrates,  and  are  distributed  by  Manson59  into  three 
genera,  as  follows : 

H^MOCYTOZOA 
i.   Genus  H^emamceba 
Names.  Hosts. 

H.  subtertiana.  The  malaria  parasites  of  man,  the  sexual 

H.  tertiana.  phase  being  evolved  in  mosquitoes  of 

H.  quartana.  the  genus  Anopheles. 

H.  relicta  (Proteosoma).  Birds;    sexual    phase    in   mosquitoes    of 

the  genus  Culex. 

H.  Danielewski  (Halteridium).  Birds. 

H.  Kochi.  Several  species  of  monkeys. 

H.  melaniphera.  Bat   (Miniopterus  Shreibersii). 

H.  Metchnikovi.  Trionyx  indicus. 

2.  Genus  Piroplasma 


P.  bigeminum. 

P.  canis. 
P.  ovis. 
P.  equi. 
P.  hominis. 

Bovines ;   transmitted  by  the   cattle  tick 

(Boophilus  bovis). 
Dogs. 
Sheep. 
Horse. 
Man. 

3.  Genus 

H^EMOGREGARINA 

H.  ranarum   (Drepanidium). 
H.  splendens. 
H.  magna. 
H.  lacertarum. 

Frog   (Rana  esculenta). 
Frog    (Rana  esculenta). 
Frog    (Rana  esculenta). 
Lizard  (Lacerta  muralis). 

About  twenty  additional  but  less  readily  procured  species. 

There  are  three  sharply  defined  species  of  parasites  of  mala- 
ria, the  parasite  of  tertian  malaria,  the  parasite  of  quartan 
malaria,  and  the  parasite  of  estivo-autumnal  malaria.  The 
latter  is  divided  by  most  observers  into  three,  or  at  least  two, 
varieties,  the  tertian  and  the  quotidian,  of  which  latter  variety 
a  pigmented  form  and  an  unpigmented  form  are  described. 
The  writer's  opinion  is  that  there  are  two  varieties  of  the 
estivo-autumnal  parasite,  the  tertian  and  the  quotidian,  and 
that  the  pigmented  and  the  unpigmented  quotidians  are  merely 
forms  of  one  variety. 


ETIOLOGY 


IJ3 


A  number  of  students  of  malaria,  with  Laveran  at  their 
head,  maintaining  the  unity  of  the  malarial  parasites,  hold 
that  the  several  species  are  only  forms  of  one  species  which 
may  be  mutually  transformed.     The  arguments  upon  which 


Fig.  45- — Diagram  illustrating  the  cycles  of  the  parasite. 
—  .  — .  —  .  —  .  Schizogonic  cycle. 

Spbrogonic  cycle. 

Parthenogenetic  cycle. 

their  theory  is  based  are  so  unsound  in  the  light  of  our  present 
knowledge  that  it  is  unnecessary  to  review  them. 

Biology. — The  life  history  of  the  parasites  of  malaria  is 
somewhat  complicated,  inasmuch  as  man,  the  mosquito,  and 


114  THE   STUDY   OF   MALARIA 

the  parasite  are  involved,  and  as  there  are  three  species  of 
parasites  and  each  species  has  three  biologic  cycles.  These 
three  cycles  are: 

1.  The  schizogonic,  or  human  cycle,  also  called  the  asexual 
cycle,  monogonic  cycle,  endogenous  cycle,  cycle  of  Golgi,  or 
trophic  cycle. 

2.  The  sporogonic  or  mosquito  cycle,  also  called  the  sexual 
cycle,  amphigonic  cycle,  exogenous  cycle,  or  cycle  of  Ross. 

3.  The  parthenogenetic  cycle,  or  reproduction  by  unfertilized 
macrogametes ;  the  cycle  of  chronic  malaria,  of  latency  and  re- 
lapses, an  immaculate  conception  yielding  saviours  to  the  spe- 
cies necessary  for  its  salvation  at  a  time  of  crisis,  a  vicarious 
atonement  of  macrogametes  that  the  human  cycle  may  be 
saved. 

The  first  cycle  is  that  of  active  malaria;  the  last  two  are 
destined  for  the  perpetuation  of  the  species,  and  without  them 


Fig.  46. — The  entrance  of  the  sporozoit  into  the  red  cell. 

the  interruption  of  the  schizogonic  cycle  would  result  in  the 
extermination  of  the  species. 

The  Schizogonic  Cycle. — In  the  act  of  biting  the  mosquito 
injects  into  the  blood  sporozoits,  elongated  or  needle-shaped 
organisms.  The  sporozoits  have  the  power  of  bending,  con- 
traction, and  of  locomotion,  and  each  immediately  penetrates 
into  a  red  blood-cell  (Fig.  46).  Here  it  loses  its  slender  form 
and  appears  as  a  mere  dot  of  protoplasm,  whose  index  of  re- 
fraction varies  but  little  from  that  of  the  red  cell.  The  size 
of  the  young  parasite  varies  in  different  species,  but  is  about 
1  or  2  microns  in  diameter.  Ameboid  motion  is  more  or  less 
active,  pseudopodia  being  protruded  and  retracted,  the  parasite 
even  changing  its  position  within  the  cell,  and  has  no  constant 
form.    There  is  usually  only  one  parasite  in  each  infected  cell, 


ETIOLOGY 


"5 


but  there  may  be  several.  As  the  parasite  grows  it  acquires 
pigment,  a  few  grains  at  first,  gradually  increasing  in  amount 
with  the  growth  of  the  parasite.  This  pigment  is  from  the 
hemoglobin  of  the  infected  cell,  and  occurs  in  the  form  of 
grains,  rods,  or  clumps.  The  adult  parasite  occupies  a  rela- 
tively large  portion  of  the  cell,  and  ameboid  motion  is  less 
active,  though  the  pigment  may  be  in  violent  motion.  The 
organism  is  composed  of  cell  protoplasm,  nucleus,  and  nucle- 
olus, but  appears  structureless  in  fresh,  unstained  blood.  Prior 
to  sporulation  the  pigment  becomes  concentrated  and  fused, 
and  fission  occurs,  dividing  the  parasite  more  or  less  symmetri- 
cally into  spores,  constituting  the  so-called  rosette  or  mar- 
guerite forms,  each  spore  containing  a  fragment  of  nucleus. 


© 


Jo 


Fig.  47. — Diagram  representing  the  development  of  the  malarial  parasite  :  a,  Young 
form  ;  b,  half-grown  parasite  ;  c,  sporulating  body  ;  d,  free  spores  ;  e,  macrogamete  ; 
/,  microgametocyte. 

The  cell  ruptures  and  the  spores,  or  merozoites,  escape  into  the 
blood  current,  where  they  rapidly  enter  the  blood-cells  to  repeat 
the  cycle.  The  corpuscular  remnants  and  the  pigment  are 
rapidly  taken  up  by  the  phagocytes. 

Instead  of  proceeding  to  sporulation  some  of  the  parasites 
develop  into  sexual  forms,  or  gametes,  large  parasites  of  round, 
ovoid,  spindle,  or  crescentic  shape.  It  is  these  bodies  which 
are  taken  up  by  the  mosquito,  undergo  a  sexual  cycle  in  its 
midgut,  develop  into  sporozoits,  which  are  injected  into  man, 
where  they  pass  through  the  schizogonic  cycle  above  outlined. 

The  Tertian  Parasite  (Hamamceba  vivax,  H.  tertiana, 
Plasmodium  vivax). — The  duration  of  the  asexual  cycle  of 
the  simple  tertian  parasite  is  forty-eight  hours.     The  young 


Il6  THE   STUDY   OP  MALARIA 

parasites  are  about  one-fifth  the  size  of  the  red  blood  corpus- 
cles and  unpigmented.  They  are  difficult  to  distinguish  from 
the  young  parasites  of  the  other  species.  They  are  actively 
ameboid,  protruding  and  retracting  short  pseudopodia  with 
rapidity;  Y-shapes,  T-shapes,  and  crosses  are  common  forms. 
The  index  of  refraction  of  the  parasites  is  low,  so  that  their 
contours  are  not  clearly  distinguished  from  the  substance  of 
the  red  blood-cells.  As  the  parasite  increases  in  size  pigment 
gradually  appears.  The  pigment  of  the  tertian  parasite  is  fine, 
rod-shaped,  rather  light  in  color,  and  in  active  motion.  This 
motion  of  the  pigment  has  been  compared  to  the  bubbling  of 
boiling  water  and  to  the  swarming  of  insects.  The  infected 
red  cell  becomes  enlarged,  swollen,  and  pale.  The  half -grown 
parasite  fills  about  half  or  two-thirds  of 'the  red  blood  cor- 
puscle. At  this  stage  the  parasite  assumes  fantastic  and  bizarre 
shapes.  The  adult  parasite  is  more  or  less  spherical,  as  large 
as  or  larger  than  a  normal  red  cell,  and  occupies  three-fourths 
or  four-fifths  of  the  swollen  infected  cell,  the  margin  of  which 
may  be  difficult  to  see  on  account  of  its  pale  color.  The  pig- 
ment tends  to  become  more  abundant  about  the  periphery. 
When  sporulation  is  imminent  the  parasite  and  its  pigment 
becomes  less  active  or  motionless,  the  pigment  gathers  in 
clumps  at  the  center,  and  radial  striations  appear  from  the 
periphery  toward  the  center.  Usually  the  sporulating  tertian 
parasite  is  not  so  symmetrical  as  the  corresponding  stage  of 
the  quartan,  resembling,  rather,  a  bunch  of  grapes  or  a  mul- 
berry. Less  often  there  are  two  concentric  rows  of  spores. 
The  spores  are  small  and  oval  and  vary  in  number  from  twelve 
or  fourteen  to  twenty-six,  oftenest  sixteen,  and  more  often  an 
even  than  an  uneven  number.  Sporulation  takes  place  espe- 
cially in  the  circulation  of  certain  viscera,  but  sporulating  ter- 
tian parasites  are  much  more  frequently  encountered  in  the 
peripheral  circulation  than  in  the  case  of  estivo-autumnal  infec- 
tions. 

The  parasites  develop  with  remarkable  uniformity,  nearly 
all  appearing  to  be  of  the  same  age.  Even  in  infections  with 
two  groups  of  tertian  parasites,  which  is  very  common,  it  is 
unusual  to  find  a  parasite  which  does  not  belong  to  one  brood. 


DESCRIPTION    OF   PLATES    II    AND    III 


Various  forms  01  malarial  parasites:  Figs,  i  to  10  inclusive,  tertian  parasites; 
Figs,  ii  to  19  inclusive,  quartan  parasites;  Figs.  20  to  26  inclusive,  estivo- 
autumnal  parasites. 

1. — Normal  red  blood  cell.  2. — Young  tertian  ring.  3. — Large  tertian  ring. 
4. — Half -grown  tertian  parasite.  5. — Infected  cell  showing  Schiiffner's  dots. 
6. — Adult  tertian  parasite.  7. — Beginning  sporulation.  8. — Sporulation  com- 
pleted. 9. — Tertian  microgametocyte.  10. — Tertian  macrogamete.  11. — Young 
quartan  ring.  12. — Older  quartan  ring.  13. — Quartan  band.  14. — Older 
quartan  band.  15. — Full-grown  quartan  parasite.  16. — Mature  parasite  with 
divided  chromatin.  17. — Sporulation  completed.  18. — Quartan  microgameto- 
cyte. 19. — Quartan  macrocyte.  20. — Young  estivo-autumnal  ring.  21. — Large 
estivo-autumnal  ring.  22. — Mature  parasite.  23. — Sporulation  completed. 
24. — Estivo-autumnal  microgametocyte.  25. — Estivo-autumnal  macrogamete. 
26. — Estivo-autumnal  ovoid. 


PLATE  II 


O 


:.« i 


'?£& 


.•*  ' 


■ 


•  /*> 


0 


C 


10 


11 


12 

Deaderick  Del. 


PLATE  III 


**    *  :  W   *i 


,  • .  i  - 


13 


14 


J5 


•>?.; 

■'  V'"' 

ft 


i6 


17 


18 


19 


o 


20 


21 


22 


i  -r'- 


#.-.- 
,'.j» 


23 


24- 


25 


26 


Deaderick  Del. 


ETIOLOGY  117 

The  early  development  of  the  gametes  is  not  well  under- 
stood. Half -grown  gametes  are  hard  to  differentiate  from 
schizonts,  but  small  parasites,  without  ameboid  motion,  with 
much  pigment,  and  with  large  nucleus  may  be  regarded  as 
gametes.  The  adult  gamete  resembles  the  full-grown  schizont. 
In  shape  it  is  more  or  less  spherical  and  may  be  twice  as  large 
as  a  red  blood  corpuscle.  Ameboid  movement  is  very  slight, 
the  pigment  is  profuse,  fine,  reddish,  or  blackish,  and  actively 
motile.  The  vesicular  appearing  nucleus  is  commonly  situated 
near  the  periphery,  and  is  visible  in  fresh  preparations. 

An  interesting  phenomenon  which  occurs  in  the  case  of  the 
microgametocytes,  or  male  sexual  forms,  is  exflagellation. 
This  takes  place  from  ten  to  thirty  minutes  after  the  blood  has 
been  withdrawn,  and  is  favored  by  exposing  the  blood  for 
a  few  minutes  to  the  air,  by  the  addition  of  a  minute  quantity 
of  water,  and  exposure  to  moisture,  as  breathing  upon  the 
slide  before  applying  the  cover-glass.  Before  exflagellation 
the  pigment  is  observed  to  undergo  violent  and  tumultuous 
motion,  then  to  collect  toward  the  center.  Undulations  at  the 
periphery  are  then  noted,  as  if  something  within  were  trying 
to  escape.  Suddenly  the  flagella  break  forth  from  different 
points  of  the  margin.  These  are  from  four  to  eight  in  number 
and  in  length  are  two  and  a  half  to  three  times  the  diameter  of 
the  red  blood  corpuscle.  They  may  show  ovoid  swellings  at 
the  end  or  in  their  continuity.  Lashing  madly  to  and  fro,  the 
red  cells  are  displaced  and  a  flagellum  may  be  seen  to  break 
off  from  the  microgametocyte  and  dart  in  a  serpentine  manner 
among  the  cells.  The  flagella  are  known  as  microgametes, 
and  have  been  shown  by  McCallum  to  be  spermatozoa.  Their 
function  is  to  fertilize  the  macrogametes,  or  female  forms,  in 
the  midgut  of  the  mosquito. 

Tertian  gametes  may  be  distinguished  from  adult  schizonts 
by  the  former  being  of  larger  size,  less  ameboid  motion,  their 
pigment  appearing  earlier,  being  more  abundant  and  in  more 
active  motion. 

The  following  may  serve  to  differentiate  tertian  male  and 
female  srametes : 


Il8  THE   STUDY  OF   MALAEIA 

Microgametocytes.  Macrogametes. 

Plasma  hyaline.  Plasma  granular. 

Pigment    abundant,    in    thick  rods,      Pigment  in  fine  rods  and  granules, 

brownish  yellow.  brownish  black. 
Not   larger   than   a   red   blood-cell.      Larger  than  a  red  cell. 

Chromatin   profuse.  Chromatin  less  abundant. 

Little  ameboid  motion.  More  or  less  ameboid  motion. 

Nucleus  toward  center.  Nucleus  toward  periphery. 

In  stained  films  the  early  stage  of  the  tertian  parasite  is 
seen  as  a  ring.  Often  the  ring  is  not  of  the  same  thickness 
throughout  its  circumference,  but  is  composed  of  a  thin  seg- 
ment, and  a  thicker  segment,  the  chromatin,  being  upon  the 
thin  segment.  Usually  the  chromatin  dot  is  immediately  within 
the  ring,  but  may  lie  outside,  and  is  surrounded  by  a  pale  zone. 
The  achromatic  zone  may  be  regarded  as  the  nucleus  and  the 
chromatin  as  the  nucleolus.  As  the  parasite  develops  one  arc 
becomes  much  thickened,  giving  the  appearance  of  the  signet 
ring.  The  forms  of  the  half-grown  parasite  are  varied  and 
peculiar.  Pigment  appears  first  and  most  abundantly  in  the 
peripheral  region,  and  does  not  invade  the  clear  zone.  The 
red  cell  is  enlarged  and  does  not  stain  deeply.  A  peculiar 
stippling  of  the  infected  red  cells  is  shown  in  films  containing 
tertian  parasites  and  stained  with  the  Romanowsky  stain  or 
one  of  its  modifications.  When  the  parasite  fills  one-third  of 
the  cell  a  number  of  fine,  red-stained  points,  SchiifTner's  dots, 
appear,  which  increase  in  size  but  not  in  number  as  the  parasite 
grows.  In  the  process  of  sporulation  the  chromatin  becomes 
subdivided  and  surrounded  by  a  clear  zone  and  encircled  by 
the  blue  cytoplasm,  constituting  the  spore. 

The  Quartan  Parasite  (H (Entamoeba  malaria;,  H.  quartance, 
Plasmodium  malaria,  Laverania  malarice). — The  duration  of 
the  schizogonic  cycle  of  the  quartan  parasite  is  seventy-two 
hours.  The  young  forms  of  the  parasite  appear  as  small, 
hyaline,  unpigmented  bits  of  protoplasm.  They  are  highly 
refractive  and  the  contour  is  much  more  sharply  defined  than 
the  tertian  parasite.  Ameboid  motion  is  sluggish  and  the 
organism  may  be  watched  some  time  until  motion  is  detected. 
Pigment  appears  within  twenty-four  hours.  It  is  in  larger 
quantities  than  in  the  tertian  parasite,  in  coarser  grains  or  rods, 
and  dark  brown  or  black  in  color.     The  pigment  is  accumu- 


ETIOLOGY  119 

lated  around  the  margin,  and  its  motion  is  very  slow.  In  the 
half-grown  parasites  the  peculiar  forms  observed  in  the  tertian 
organisms  are  not  seen,  and  ameboid  movements  become  more 
sluggish  or  cease  altogether.  The  red  blood-cell  infested  with 
the  quartan  parasite  does  not  enlarge  and  decolorize  as  in 
tertian  infections,  but,  if  there  is  any  deviation  from  normal, 
becomes  smaller  and  darker,  perhaps  greenish  and  brassy.  The 
adult  parasites  are  almost  as  large  as  the  red  cells.  Prior  to 
sporulation  the  pigment  collects  toward  the  center,  often  in 
a  radial  arrangement.  Sporulation  proceeds  after  the  manner 
of  the  tertian  parasite,  but  is  slower.  The  sporulating  forms 
are  beautifully  symmetrical,  and  are  typical  rosettes.  The 
spores  are  round  or  oval,  relatively  large  and  six  to  twelve  in 
number,  oftenest  eight.  Sporulating  quartan  parasites  are 
much  more  commonly  observed  in  the  peripheral  blood  than 
are  the  corresponding  forms  of  the  other  species. 

Quartan  gametes  are  but  rarely  encountered.  The  macro- 
gametes  are  spherical  in  shape,  and  as  long  as  they  remain 
intracorpuscular  are  smaller  than  tertian  gametes,  but  are 
equally  as  large  when  they  become  extracorpuscular.  Ex- 
flagellated  microgametocytes  have  been  observed;  they  are 
somewhat  smaller  than  the  tertian  forms,  but  no  less  active. 

The  staining  reactions  of  the  quartan  parasite  are  similar 
to  those  of  the  tertian.  The  young  form  is  a  ring  and  so 
closely  resembles  the  tertian  that  it  cannot  be  distinguished  with 
certainty.  After  twelve  to  twenty-four  hours  the  parasite  be- 
comes disc  or  band  shaped.  The  latter  forms  are  character- 
istic. The  parasite  extends  across  the  center  of  the  infested 
cell  as  a  more  or  less  broad  band,  often  rather  quadrilateral, 
the  pigment  being  arranged  more  profusely  along  the  margin 
of  the  band.  The  chromatin  body  of  the  quartan  species  stains 
less  intensely  and  splits  earlier  than  in  the  tertian.  The  adult 
usually  fills  the  corpuscle,  which  may  be  no  longer  apparent. 
The  sexes  of  the  gametes  are  differentiated  by  the  same  char- 
acters as  in  the  tertian. 

The  Estivo-autumnal  Parasite  (Hccmamccba  prcecox, 
Plasmodium  prcecox,  Hccmamccba  immaculata,  Laverania  pre- 
cox, Hcemomenas  prcecox,  Plasmodium  immaculatum,  Hcema- 


120  THE   STUDY   OF   MALARIA 

mceba  parva,  Hcematozoon  falciform,  Plasmodium  falciparum). 
— The  young  forms  of  the  estivo-autumnal  parasites  are  similar 
to  those  of  the  other  species,  but  are  smaller,  being  from  one- 
fifth  to  one-sixth  the  size  of  the  infested  corpuscle.  Ameboid 
motion  is  rather  active,  stars,  crosses,  and  irregular  shapes 
occurring  in  succession.  At  rest  the  parasites  appear  annular 
or  discoid.  More  than  one  parasite  in  a  single  cell  is  rela- 
tively more  common  than  in  tertian  and  quartan  infections. 
Advanced  stages  of  development  are  rarely  seen  in  peripheral 
blood.  The  infested  red  cells  often  become  shrivelled,  cre- 
nated,  darker,  and  of  a  brassy  hue.  The  adult  parasites  do 
not  attain  the  size  of  the  red  blood  corpuscles.  Sporulation 
proceeds  in  a  manner _  similar  to  that  of  the  simple  tertian 
parasite.  The  spores  number  from  five  to  twenty-five  or  even 
thirty.  Sporulation  is  not  so  uniform  as  in  the  other  infec- 
tions; sporulating  forms  may  be  associated  with  young  or 
half-grown  parasites. 

Estivo-autumnal  gametes  occur  in  the  form  of  crescents, 
and  of  fusiform,  ovoid,  and  spherical  bodies.  The  crescent  is 
characteristic,  being  found  in  this  form  of  malaria  alone.  They 
are  cylindrical,  tapering  slightly  at  each  extremity,  and 
slightly  curved  upon  themselves.  They  are  longer  than  the 
diameter  of  the  red  cell  and  about  a  third  as  broad  as  long. 
The  changes  from  crescent  to  ovoid  and  round  bodies  may 
be  easily  observed  under  the  microscope.  The  gametes  appear 
only  after  the  infection  has  persisted  for  about  a  week.  The 
crescent  may  lie  within  the  cell  or  may  have  the  appearance 
of  the  red  cell  being  attached  to  the  concave  side;  in  some 
instances  there  is  no  evidence  left  of  the  infested  blood-cell. 
The  cell  may  be  stretched  across  the  concavity  of  the  crescent, 
and  is  usually  almost  decolorized.  The  crescents  have  given 
evidence  of  a  double  outline.  They  possess  no  ameboid  move- 
ment, and  the  pigment  in  the  form  of  rods  or  granules  is 
motionless.  Before  exflagellation  the  crescent  assumes  the 
spherical  form,  smaller  than  the  tertian,  and  similar  to  the 
quartan. 

The  staining  reactions  of  the  estivo-autumnal  schizonts  are 
similar  to  those  of  the  tertian  and  quartan.     The  young  para- 


DESCRIPTION    OF   PLATES    IV   AND    V1 


The  drawings  were  made  with  the  assistan  of  the  camera  lucida  from  specimens  of  fresh 
Mood.  A  Winckel  microscope,  objective  %  (oil  immersion),  ocular  4,  was  used.  Figures  4, 13,  23, 
24,  and  42  of  Plate  IV  were  drawn  from  fresh  blood,  without  the  camera  lucida. 

PLATE   IV 
The  Parasite  of  Tertian  Fever. 

1. — Normal  red  corpuscle. 

2,  3,  4.— Young  hyaline  forms.    In  4,  a  corpuscle  contains  three  distinct  parasites. 

5,  21. — Beginning  of  pigmentation.  The  parasite  was  observed  to  form  a  true  ring  by  the  con- 
fluence of  two  pseudopodia.  During  observation  the  body  burst  from  the  corpuscle,  which  became 
decolorized  and  disappeared  from  view.  The  parasite  became,  almost  immediately,  deformed  and 
motionless,  as  shown  in  Fig.  21. 

6,  7,  8. — Partly  developed  pigmented  forms. 
9. — Full-grown  body. 

10-14. — Segmenting  bodies. 

15. — Form  simulating  a  segmenting  body.  The  significance  of  these  forms,  several  of  which 
have  been  observed,  was  not  clear  to  Drs.  Thayer  and  Hewetson,  who  had  never  met  with  similar 
bodies  in  stained  specimens  so  as  to  be  able  to  study  the  structure  of  the  individual  segments. 

16,  17. — Precocious  segmentation. 

18,  19,  20. — Large  swollen  and  fragmenting  extracellular  bodies. 

22.— Flagellate  body. 

23,  24.— Vacuolization. 

The  Parasite  of  Quartan  Fever. 

25. — Normal  red  corpuscle. 
26. — Young  hyaline  form. 

27-34. — Gradual  development  of  the  intracorpuscular  bodies. 

35.— Full-grown  body.  The  substance  of  the  red  corpuscle  is  no  more  visible  in  the  fresh 
specimen. 

36-39.— Segmenting  bodies. 

40. — Large  swollen  extracellular  form. 

41.— Flagellate  body. 

42. — Vacuolization. 

PLATE  V 
The  Parasite  of  ^Estivo-autumnal  Fever. 

1,  2. — Small  refractive  ring-like  bodies. 

3-6.— Larger  disk-like  and  ameboid  forms. 

7.— Ring-like  body  with  a  few  pigment-granules  in  a  brassy,  shrunken  corpuscle. 

8,  9,  10,  12. — Similar  pigmented  bodies. 

11. — Ameboid  body  with  pigment. 

13. — Body  with  a  central  clump  of  pigment  in  a  corpuscle,  showing  a  retraction  of  the  hemo- 
globin-containing substance  about  the  parasite. 

14-20. — Larger  bodies  with  central  pigment  clumps  or  blocks. 

21-24.— Segmenting  bodies  from  the  spleen.  Figs.  21-23  represent  one  body  where  the  entire 
process  of  segmentation  was  observed.  The  segments,  eighteen  in  number,  were  accurately 
counted  before  separation,  as  in  Fig.  23.  The  sudden  separation  of  the  segments,  occurring  as 
though  some  retaining  membrane  were  ruptured,  was  observed. 

25-33.— Crescents  and  ovoid  bodies.  Figs.  30  and  31  represent  one  body,  which  was  seen  to 
extrude  slowly,  and  later  to  withdraw,  two  rounded  protrusions. 

34,  35. — Round  bodies. 

36. — "  Gemmation,"  fragmentation. 

37. — Vacuolization  of  a  crescent. 

38-40. — Flagellation.  The  figures  represent  one  organism.  The  blood  was  taken  from  the  ear 
at  4.15  p.  m. ;  at  4.17  the  body  was  as  represented  in  Fig.  38.  At  4.27  the  flagella  appeared  ;  at  4.33 
two  of  the  flagella  had  already  broken  away  from  the  mother  body. 

41-45. — Phagocytosis.    Traced  with  the  camera  lucida. 

1  These  illustrations  are  reproduced  by  permission  from  the  article  by  Drs.  Thayer  and  Hewet- 
son in  The  Johns  Hopkins  Hospital  Reports,  vol.  v.,  1895. 


PLATE  IV 

The  Parasite  of  Tertian  Fever. 


■ 


«ij 


«" 


4^f 


■■/■^ 


*$$& 

<**$ 


'X 


The  Parasite  of  Quartan  Fever. 


V/ 


ft 


# 


+2 


si    >    Ji 
*■.  L'.» 


PLATE  V 

The  Parasite  of  Aestivo  Autumnal  Fever 


*& 


* 


S2 


2<f- 


o 


O 


u 


37 


:- a 


^ 


^ 


*3 


♦4 


i^"> 
<*,,/ 


o 


•c* 


*i* 


ETIOLOGY 


121 


sites  are  unpigmented  rings,  resembling  the  simple  tertian 
rings,  but  are  smaller  and  more  delicate.  Typical  signet  rings 
and  rings  without  nodes  are  seen.  The  ring  may  be  distorted 
or  become  broken  and  extended  like  a  delicate  thread  or  a 
narrow  band.  The  largest  rings  are  about  one-half  the  diam- 
eter of  the  red  cell.  The  pigment  is  sparse.  Both  the  sporu- 
lating  body  and  the  individual  spores  are  small.  The  central 
region  of  the  crescent  is  almost  achromatic,  the  extremities 
staining  more  deeply.  Chromatin  is  not  always  visible  in  the 
crescents,  but  is  usually  seen,  as  is  the  pigment,  in  the  achro- 
matic area. 

Mixed  infections  with  quotidian  and  tertian  estivo-autumnal 
parasites  are  very  common. 

The  differences  between  these  parasites  are  thus  tabulated 
by  Craig  :70 


The   Hyaline   Body 


Stage  of  Develop- 
ment. 

Quotidian. 

Size. 

Minute,  one-sixth  of 
corpuscle. 

Shape. 

Ring  or  perfectly  round. 

Outline. 

Indistinct. 

Motion. 

Very  active. 

Corpuscle. 

Very  dark  green,  wrin- 
kled.    Crenated. 

Number. 

More  than  one  parasite 
in  a  corpuscle,  com- 
mon. 

Malignant  Tertian. 

Larger,  one-third  to  one- 
quarter  of  corpuscle. 

Signet-ring  shape. 

Clear  cut  and  refractive. 

Sluggish. 

Light  green,  less  wrin- 
kled. 

Very  seldom  more  than 
one  parasite  in  a  cor- 
puscle. 


Size. 
Shape. 

Motion. 
Outline. 

Pigment. 

Number. 
Corpuscle. 


The  Pigmented  Body 

One-quarter  size  of  cor- 
puscle. 

Round.  Loses  ring  form 
before  pigmentation. 

Ameboid  motion  is  lost. 

More    sharply    defined. 


One  or  two  coarse  gran- 
ules, perfectly  motion- 
less. 

May  be  more  than  one 
in  a  corpuscle. 

Very  green  in  color, 
often  crenated. 


One-half  size  of  corpus- 
cle. 

Ring  form  becomes  pig- 
mented, afterward  the 
parasite  is  round. 

Ameboid  motion  con- 
tinues.    Is  sluggish. 

Very  sharply  defined  and 
refractive.  The  proto- 
plasm firmly  granular. 

Several  minute  grains, 
having  a  rapid  vibra- 
tory motion. 

Never  more  than  one  in 
a  corpuscle. 

Lighter  in  color,  seldom 
crenated. 


122 


THE   STUDY   OF  MALARIA 


Place  of  segmen- 
tation. 

Number  of  seg- 
ments. 

The  crescent  phase. 


Cycle    of    develop- 
ment. 


The  Segmenting  Body 
Within    the    red    blood-      Outside   the    red   blood- 


corpuscles,  as  a  rule. 
Six  to  eight. 


Crescents  small  and 
plump,  containing  small 
amount  of  pigment. 
Always  present  double 
outline. 

Twenty-four  hours. 


corpuscles,  as  a  rule. 
Ten  to  fifteen  or  more. 


Crescents  long,  narrow, 
deeply  pigmented.  Dou- 
ble   outline    less    com- 


Forty-eight  hours. 


The  following  table  will  serve  to  distinguish  the  sexes  of 
the  gametes : 


Microgametocytes. 
Protoplasm  stains  very  slightly. 
Pigment  distributed  throughout  the 

parasite. 
Reniform,  short,  and  broad. 
Chromatin      in      several      scattered 


Macrogametes. 
Protoplasm  stains  more  intensely. 
Pigment  collected  near  center,  often 

in  a  circle. 
Crescentic,  longer  and  narrower. 
Chromatin    in    one    or    two    large 

masses  near  the  center. 


The  chief  characteristics  of  the  species  of  malarial  parasites 
may  be  tabulated  as  follows : 


Tertian. 

Quartan. 

Estivo-autumnal. 

Length  of  asexual 

48  hours. 

72  hours. 

24       hours,       48 

cycle. 

hours,     or     ir- 
regular. 

Site  of  sporulation. 

May  sporulate  in 

Equally    in    peri- 

Visceral   circula- 

peripheral 

pheral  and  vis- 

tion. 

blood,       chiefly 

ceral   blood. 

in  visceral  cir- 

culation. 

Movements. 

Active. 

Sluggish. 

Active. 

Pigment. 

Fine,       yellowish 

Coarse,      dark 

Scanty,  fine. 

or  dark  brown, 

brown  or  black 

scattered,      ac- 

(at periphery), 

tively  motile. 

slightly    motile. 

Effect  on  red  cell. 

Enlarged,     decol- 

Normal   size    or 

Often     shrunken, 

orized,    Schtiff- 

smaller,     often 

may     be     dark 

ner's     dots     in 

dark      and 

and  brassy. 

stained  films. 

brassy. 

Size  of  adult. 

As  large  as  nor- 

Smaller      than 

Much      smaller 

mal     red     cor- 

normal corpus- 

than    normal 

puscles. 

cles. 

corpuscles. 

Sporocyte. 

Mulberry  shape. 

Symmetrical 
daisy  shape. 

Irregular. 

Spores. 

12-26,        oftenest 

16. 
Spherical. 

6-12,    oftenest    8. 

5-30. 

Gametes. 

Spherical. 

Crescentic. 

It  is  not  infrequently  difficult  to  differentiate  young  tertian 
from  young  estivo-autumnal  rings,  though  the  following  table, 


ETIOLOGY  123 

adapted  from  Ewing,130  will  enable  a  comparison  of  the  main 
features : 

Tertian.  Estivo-autumnal. 

Nucleus    achromatic   to    methylene-      Nucleus  stains  intensely  with  methy- 

blue.  lene-blue. 

Ring  usually  coarse  and  irregular.       Ring    geometrically    circular,    deli- 
cate, usually  a  typical  signet-like 
swelling. 
One  or  two  grains  of  pigment  al-      Pigment    almost    constantly   absent. 

most  invariably  present.  . 

Ring     usually     pigmented     before      Chromatin  always  subdivides  betore 

chromatin  subdivides.  pigment  appears. 

Infected  cell  swollen.  Infected  cell  shrunken. 

The  Sporogonic  Cycle.— If  the  anopheline  mosquito  ob- 
tains blood  containing  only  schizonts,  the  latter  soon  perish  in 
the  digestive  canal  of  the  insect.    However,  if  the  blood  con- 
tains mature  gametes  of  both  sexes  these  undergo  the  exogen- 
ous cycle,  to  be  prepared  to  reinfect  man  bitten  by  the  infected 
mosquito.     The  portion  of  the  mosquito  in  which  this  trans- 
formation takes  place  is  the  stomach  or  midgut.    Shortly  after 
the  infested  blood  has  been  sucked  into  the  stomach  the  micro- 
gametocytes  exflagellate,  the  microgametes  become  free,  and 
the  macrogametes  emit  small  protuberances  to  receive  the  fla- 
gella  or  spermatozoa.     The  latter  forces  an  entrance  into  the 
macrogamete  at  the  site  of  the  protuberance,  and  the  resulting 
fertilized  body  is  known  as  the  zygote.    All  this  has  taken  place 
within  the  first  few  hours.     In  its  early  stages  the  zygote  re- 
sembles the  ovoid  body,  but  is  larger.     It  is  pigmented,  it  en- 
larges, becomes  pyriform,  and  has  the  power  of  locomotion. 
The  zygote  burrows  through  the  epithelial  coat  of  the  midgut 
to  the  tunica  elasticomuscularis,   becomes  spherical  and  en- 
cysted, and  is  known  as  the  oocyst.     It  enlarges  so  that  it 
projects  like  a  spherical  excrescence  into  the  body  cavity  or 
blood  sinus,  where  it  is  nourished.     The  stomach  of  a  badly- 
infected  mosquito  may  be  studded  with  these  outgrowths.   The 
oocyst  attains  a  size  of  40  to  70  microns  in  diameter.     Its 
nuclear  chromatin  divides  and  subdivides,  each  portion  sur- 
rounded by  protoplasm,  polygonal  or  irregular  in  shape  from 
pressure,  being  known  as  the  sporoblast.     Each   sporoblast 
splits  into  a  large  number  of  sporozoits,  each  enclosing  a  bit 
of  chromatin.     The  sporozoits  remain  attached  by  one  end  to 


124  THE   STUDY   OF   MALARIA 

the  residual  body  of  the  sporoblast  until  the  oocyst  bursts,  when 
the  sporozoits  escape  into  the  body  cavity.  Finally,  through 
the  lacunar  circulation,  they  arrive  at  the  salivary  glands, 
where  they  congregate  in  hordes.  The  sporozoits  number 
from  a  few  hundreds  to  ten  thousand  or  more,  each  measures 
about  14  microns  in  length,  about  eight  times  as  long  as  broad, 
being  very  slender,  tapering  at  both  ends,  and  endowed  with 
serpentine  movements.  From  the  salivary  glands  the  sporo- 
zoits are  injected  by  the  mosquito,  in  the  act  of  preying  upon 
its  victims,  where  each  sporozoit  soon  enters  a  red  cell  and  goes 
through  the  schizogonic  cycle.  The  duration  of  the  mosquito 
cycle  varies  from  eight  to  sixteen  or  more  days,  depending 
mainly  upon  the  temperature,  but  possibly  also  upon  other 
factors. 

The  three  species  of  parasites  are  closely  similiar  in  their 
stages  of  exogenous  development.  The  differences  between 
the  tertian  and  the  estivo-autumnal  organisms  are  that  in  the 
former  the  zygote  is  round  or  oval  instead  of  pyriform  or 
ovoid,  the  protoplasm  is  less  refractive,  the  characteristic  pig- 
ment maintains,  the  sporoblasts  are  larger  and  less  numerous, 
the  sporozoits  are  less  dense  and  more  regularly  arranged, 
often  radially  within  the  sporoblast,  and  black  spores  have  not 
been  found. 

The  quartan  parasite  is  the  most  difficult  to  develop  within 
the  mosquito. 

The  Parthenogenetic  Cycle. — Parthenogenesis,  or  virgin 
birth,  is  reproduction  by  unfertilized  females. 

This  phenomenon,  known  also  as  the  "alternation  of  genera- 
tions," has  been  most  carefully  studied  in  plant  lice,  the 
Aphides.  The  eggs,  which  are  laid  in  the  fall  and  have  hiber- 
nated, hatch  in  the  spring  into  females,  having  the  power  of 
giving  birth,  without  fertilization,  to  viviparous  young,  which 
inherit  the  faculty  of  parthenogenesis,  and  procreate  in  this 
manner  until  the  advent  of  cold  weather  or  the  failure  of 
nourishment  when  males  and  oviparous  females  are  brought 
forth.  From  these  latter,  after  copulation,  ova  are  produced, 
and  the  cycle  recommences. 

Parthenogenetic  reproduction  is  known  to  occur  in  a  number 


ETIOLOGY  125 

of  species,  as  hemoproteus,  certain  rotifera,  jelly-fish,  worms, 
entomostracea,  acarina,  and  certain  insects,  the  silk-moth,  mos- 
quitoes, gall-flies,  ants,  bees,  wasps,  chironomus,  etc. 

This  life  cycle  of  the  parasite  of  malaria  is  the  most  recently 
recognized  and  least  known  of  its  cycles.  Since  the  discovery 
of  the  parasite  the  gametes  have  been  regarded  as  closely 
allied  with  the  chronic  malaria  and  relapses.  Golgi  plainly 
stated  it  as  his  belief  that  the  crescent  was  the  parasite  of 
fevers  recurring  at  long  intervals. 

Canalis,131  in  1889,  described  and  pictured  spherical  bodies 
derived  from  crescents  in  the  act  of  sporulation.  In  1890 
Antolisei  and  Angelini132  confirmed  the  observation  of  Canalis. 
Lewkowicz132  reported,  in  1897,  that  he  had  seen  sporulating 
crescents  some  of  which  contained  as  many  as  thirty  spores. 

Grassi133  expressed  the  opinion  in  1901  that  the  parasites  of 
malaria  underwent  a  parthenogenetic  cycle  of  development 
whereby  the  species  was  perpetuated  after  the  death  of  the 
schizonts. 

He  cited  a  number  of  arguments  in  support  of  the  theory, 
and  referred  to  a  similar  process  in  other  protozoa,  Adelea, 
Trichospharium,  and  Volvox. 

It  was  Schaudinn134  who,  in  1902,  first  observed  and  cor- 
rectly interpreted  parthenogenesis  of  tertian  macrogametes. 
The  case  in  which  this  was  observed  was  that  of  Frau  Kossel, 
who,  during  the  spring  and  summer  of  several  preceding  years, 
had  suffered  occasional  paroxysms.  On  April  29  and  May  1 
two  severe  paroxysms  occurred.  At  the  height  of  the  fever 
on  May  1  the  blood  was  examined  and  tertian  parasites  found 
in  abundance;  besides  schizonts,  male  and  female  gametes 
were  numerous,  showing  that  it  was  a  typical  relapse.  During 
May  the  blood  was  examined  regularly  and  found  to  contain 
tertian  gametes  in  greater  or  less  numbers.  On  May  25,  at 
noon,  the  blood  examination  showed  no  marked  variation 
from  the  usual  findings,  except  that  the  parasites  were  some- 
what more  plentiful.  In  every  preparation  were  10-20  macro- 
gametes  and  occasional  microgametocytes.  The  temperature 
was  normal.  On  the  morning  of  May  26  a  remarkable  condi- 
tion of  the  macrogametes,  with  noteworthy  nuclear  changes, 


126  THE   STUDY   OF   MALARIA 

described  below,  were  detected.  The  blood  was  examined 
every  two  hours,  and  the  temperature  was  taken  with  the  fol- 
lowing results : 

A.  M.  Centigrade  - 

10.00 37.8 

P.  M. 

12.15 384 

2.00 37.5 

5-15 37-4 

9-15 37-0 

At  12.15  and  at  2  p.  m.  parthenogenetic  forms  were  most 
abundant.  In  the  evening,  besides  unchanged  sexual  organ- 
isms, very  young  endoglobular  schizonts  were  found. 

On  May  27  the  blood  was  examined  twice ;  at  7  a.  m.  only 
young  endoglobular  schizonts  were  found,  the  temperature 
36.8 ;  at  8  p.  m.  only  scanty,  half-grown  schizonts  were  found, 
and  the  temperature  was  37. 

On  May  28  the  typical  attack  (depending  on  asexual  sporu- 
lation)  occurred,  with  the  following  temperature  course: 

A.  M.                                                                                                                 Centigrade. 
7.OO 37-60 

10.00 39-00 

p.  M. 

12.15 39-85 

1. 15 40.75 

2.15 40.40 

3-30 39-IO 

5-15 39-00 

7.00 37-8o 

9-15 37-45 

May  29. 

A.  M. 

7.00 36-4° 

The  result  of  the  blood  examination  was  as  usual  in  such 
attacks. 

The  next  morning  most  of  the  young  parasites  were  found 
to  be  gametes.  Thus  a  true  alternation  of  generations.  It 
should  be  observed  that,  while  the  sporulation  of  the  unfer- 
tilized macrogametes  or  parthenogametes  (if  it  is  permissible 
to  coin  a  much-needed  term)  caused  a  slight  rise  of  tempera- 
ture, it  did  not  compare  to  the  height  reached  during  schizo- 
gonic  sporulation.  It  is  indeed  highly  probable  that  sporula- 
tion of  a  small  number  of  parthenogametes  might  occur  with- 


Fig.  48. — Parthenogenesis  of  the  tertian  parasite  (after  Schaudinn). 


ETIOLOGY  127 

out  perceptible  rise  of  temperature,  and  that  the  paroxysm 
would  ensue  only  when  sporulation  of  schizonts  occurred  in 
sufficient  numbers. 

Schaudinn134  thus  describes  the  process  of  parthenogenesis 
as  he  observed  it  in  tertian  malaria  (Fig.  48).  The  chromatin 
of  the  parthenogamete  collects  in  coarse  fragments  and  cords 
toward  one  end  of  the  bean-shaped  nucleus,  and  stains  in- 
tensely, while  the  other  somewhat  larger  half  contains  fewer 
and  smaller  chromatin  particles  and  stains  faintly.  The  nucleus 
then  divides  into  two,  one  containing  the  coarse,  deeply  staining 
chromatin,  and  the  other  the  fine,  diffusely  staining  chromatin, 
the  former  resembling  the  nucleus  of  a  schizont  before  nuclear 
proliferation.  A  constriction  may  be  perceptible  about  the 
parasite  almost  separating  a  deeply  staining,  highly  pigmented 
portion  containing  the  pale-staining  nucleus  from  a  lightly 
stained  and  less  pigmented  portion  in  which  lies  the  deeper 
stained  nucleus.  This  nucleus  now  subdivides,  and  the  portion 
of  the  plasma  in  which  it  lies  proceeds  to  sporulation  in  a 
manner  similar  to  schizogonic  sporulation,  the  spores  becom- 
ing typical  schizonts. 

Maurer,135  in  1902,  observed  sporulation  of  estivo-autumnal 
gametes,  and  construed  it  as  parthenogenesis. 

Ziemann48  believes  that  he  has  seen  parthenogenetic  repro- 
duction of  quartan  gametes. 

Bluml  and  Metz136  observed  sporulating  parthenogametes  in 
six  preparations  taken  from  5  patients  with  tertian  malaria. 
The  process  was  identical  with  that  described  by  Schaudinn. 
Young  and  sporulating  schizonts  and  young  gametes  were 
present  in  these  same  preparations. 

Are  the  parthenogametes  identical  with  true  macrogametes 
which  do  not  proceed  to  sporulation  ?  Such  a  doubt  is  hardly 
justifiable  from  a  review  of  the  scientific  studies  of  the  learned 
Schaudinn  and  of  the  other  observers  cited  above.  Craig,137 
however,  has  recently  adduced  evidence  that  latency  and  re- 
lapses are  dependent  upon  resting  bodies,  the  products  of  intra- 
corpuscular  conjugation  of  young  schizonts.  He  does  not, 
however,  follow  these  forms  further  than  the  completion  of 
conjugation,  and  while  it  is  possible  that  this  is  the  origin  of 


128 


THE   STUDY   OF   MALARIA 


the  parthenogametes,  there  is  as  yet  no  positive  evidence  that 
the  latter  are  not  true  macrogametes. 

Inasmuch  as  different  terms  are  employed  by  various  authors 
to  describe  the  morphology  of  the  malarial  parasite,  to  the 
great  confusion  of  the  student,  the  writer  has  prepared  a  brief 
glossary  of  these  terms.  The  definitions  must  not  be  taken 
in  the  wide  zoologic  sense,  but  only  as  applied  by  the  majority 
of  writers  to  the  parasite  of  malaria : 


Amphigony.     See  Sporogony. 

Amphiont.     See  Zygote. 

Androspore.     See  Microgamete. 

Antheridium.    See  Microgametocyte. 

Asexual  Cycle,  the  schizogonic  or 
human  cycle  of  parasitic  repro- 
duction. 

Blast.     See  Sporozoit. 

Blastophore.     See  Sporoblast. 

Copula.     See  Zygote. 

Crescent,  one  form  of  the  estivo- 
autumnal  gamete. 

Definitive   Sporoblast.     See   Zygote. 

Endogenous  Cycle.     See  Schizogony. 

Enhemospore.     See  Merozoite. 

Exogenous   Cycle.     See   Sporogony. 

Exotospore.     See  Sporozoit. 

Flagella,  microgametes. 

Gamete,  sexual  form  of  the  parasite. 

Gametoblast.     See  Sporozoit. 

Gametocyte,  cell  giving  origin  to 
gametes. 

Gametospore.     See  Zygote. 

Germinal  Rod.     See  Sporozoit. 

Gymnospore,  a  schizogonic  spore  or 
merozoit. 

Gynospore.     See  Macrogamete. 

Hamosporidia,  the  suborder  of  pro- 
tozoa to  which  the  malarial  para- 
site belongs. 

Human  Cycle,  the  schizogonic  or 
endogenous  cycle. 

Macrogamete,  a  female  gamete. 

Macrogametocyte,  a  female  gameto- 
cyte. 

Macrospore.     See  Macrogamete. 

Merozoite,  a  spore  the  product  of 
schizogony;  also  applied  to  the 
sporozoit  after  it  has  entered  the 
red  cell. 

Microgamete,  a  male  gamete,  flagel- 
lum,  spermatozoan. 

Microgametocyte,  a  male  gameto- 
cyte. 

Microspore.      See  Microgametocvte. 

Monogony.     See  Schizogony. 

Mcnont.     See  Schizont. 

Mosquito  Cycle,  the  sexual  or  sporo- 
gonic  cycle. 


Nomospore.     See  Merozoit. 

Ondeterospore.     See  Schizont. 

Oocyst,  an  encysted  zygote. 

Ookinete.     See  Zygote. 

Ovoid,  one  form  of  the  estivo- 
autumnal  gamete. 

Parthenogamete  (new  word),  an 
unfertilized  sporulating  macro- 
gamete. 

Parthenogenesis,  virginal  reproduc- 
tion. 

Polymitus,  an  exflagellated  micro- 
gametocyte. 

Reproductive  Cycle,  the  sporogonic 
or  mosquito  cycle. 

Schizont,  the  asexual  form  of  the 
parasite. 

Schizogony,  the  asexual,  human  or 
endogenous  cycle  of  development. 

Sexual  Cycle,  the  sporogonic,  mos- 
quito or  exogenous  cycle. 

S  perm-mother  cell.  See  Microgame- 
tocyte. 

Spore-cyst.     See  Oocyst. 

Spore-mother  cell.    See  Sporoblast. 

Sporoblast,  spherical  or  polygonal 
bodies  contained  in  the  oocyst, 
giving  origin  to  the  sporozoits. 

Sporocyte,  a  sporulating  schizont. 

Sporogony,  the  sexual  cycle  of  de- 
velopment. 

Sporont.     See  Oocyst. 

Sporozoa,  the  class  of  protozoa  to 
which  the  malarial  parasite  be- 
longs. 

Sporozoit,  a  spore  the  product  of 
sporogony. 

Syzygies,  the  products  of  conju- 
gating parasites. 

Trophic  Cycle,  the  asexual  cycle. 

Trophozoit,  a  young  intracellular 
parasite  of  asexual  origin ;  a 
merozoit  which  has  entered  the 
red  cell. 

Vermicule.     See  Zygote. 

Zooid.     See  Sporozoit. 

Zygote,  a  fertilized  macrogamete. 

Zygotoblast.     See  Sporozoit. 

Zygotomere.     See  Sporoblast. 


ETIOLOGY  129 

Cultivation  Experiments. — Coronado138  claimed  to  have 
been  successful  in  cultivating  the  malarial  parasites  from  water 
which  he  believed  infected.  He  stated  that  the  entire  cycle 
could  be  followed.  Miller80  also  believed  that  he  had  cultivated 
the  organisms.  These  experiments  have  been  repeated,  but  the 
results  could  not  be  confirmed,  hence  were  probably  incorrect. 

Sakharov,  Rosenbach,  Blumer,  Hamburger  and  Mitchel139 
succeeded  in  maintaining  the  organisms  alive  for  several  days 
in  the  bodies  of  leeches  which  had  sucked  the  blood  from 
malarial  patients.  Hamburger's  experiment  is  thus  described 
by  Thayer:98  "Mr.  Hamburger  took  the  blood  from  a  case  of 
estivo-autumnal  fever  with  quotidian  paroxysms  at  a  time  when 
only  small  ameboid  and  ring-shaped,  non-pigmented  hyaline 
bodies  were  present.  During  the  next  several  days  he  was 
able  to  distinguish  a  slight  increase  in  size  with  the  accumula- 
tion in  nearly  every  organism  of  a  few  small  motile  pigment 
granules.  On  the  eighth  day  the  organisms  were  distinctly 
visible,  each  with  a  small  group  of  slightly  motile  granules 
in  the  middle  or  at  some  point  on  the  periphery  of  the  parasite. 
The  parasites,  as  in  Dr.  Blumer's  case,  showed  no  actual 
ameboid  movement,  though  some  slight  change  of  shape  could 
at  times  be  made  out.  In  both  instances  the  parasites  acquired 
after  several  days  a  peculiar  refractive,  glistening  appearance. 
Specimens  stained  on  the  eighth  day  showed  characteristic 
ring-shaped  bodies." 

PATHOGENESIS 

Much  fanciful  speculation  has  been  indulged  in  as  to  the 
cause  of  the  paroxysms  until  Golgi  and  others  of  the  Italian 
school  showed  that  it  was  closely  connected  with  the  life  history 
of  the  malarial  parasites  (Fig.  49). 

The  paroxysm  is  not  immediately  associated  with  the  gradual 
vegetative  growth  of  the  parasite  within  the  corpuscle,  but, 
occurring  more  or  less  abruptly  as  it  does,  is  simultaneous  with 
sporulation  and  the  sudden  discharge  into  the  blood  stream  of 
a  new  generation  of  parasites.  In  what  manner  does  this 
process  produce  so  peculiar  a  phenomenon  as  the  malarial 
paroxysm?     Golgi67  was  of  the  opinion  that  it  was  dependent 


13° 


THE   STUDY   OF   MALARIA 


upon  the  entrance  into  fresh  red  cells  of  the  young  generation 
of  parasites.  This,  however,  is  shown  to  be  erroneous  by  the 
fact  that  a  properly  timed  and  adequate  dose  of  quinine  given 
before  the  chill  is  expected  does  not  prevent  the  access  though 
it  does  destroy  the  young  parasites,  preventing  their  invasion 
of  the  cells. 

The  true  explanation  of  the  origin  of  the  paroxysm  is 
through  the  agency  of  a  toxin  liberated  by  the  sporulative  act. 
The  existence  of  a  toxin,  the  product  of  the  malarial  parasite, 


Fig.  49- 


-    O     © 

-The  relation  between  the  stages  of  the  parasite  and  the  paroxysm. 


is  almost  universally  assumed  by  students  of  malaria.     The 
grounds  for  this  assumption  may  be  recounted  as  follows : 
i.  An  analogy  with  other  infectious  diseases. 

2.  Immunity ;  this  immunity  is  not  absolute,  but  that  a  rela- 
tive immunity  to  malaria  exists  there  is  no  room  for  doubt. 

3.  The   formation  of  an  antitoxin;   Ford's140   experiments 
being  conclusive  as  to  the  existence  of  such. 

4.  Degenerative  changes  in  the  kidneys,  liver,  spleen,  and 
other  organs  not  otherwise  explainable. 

5.  Blood  changes,  as  anemia  out  of  proportion  to  the  num- 


ETIOLOGY  131 

ber  of  parasites,  and  brassy  degeneration,  stippling,  and  poly- 
chromatophilia  of  the  red  cells. 

6.  Increased  toxicity  of  the  urine  and  sweat. 

7.  The  existence  of  coma  in  malaria  without  parasites  or 
pigment  in  the  brain. 

8.  The  fever  and  its  relation  to  parasitic  sporulation. 

9.  Experimental  proof.  The  negative  results  of  Gualdi,79 
Montesano,79  Mannaberg,14w  and  Celli80  are  devoid  of  weight 
against  the  convincing  experiments  of  Rosenau,  Parker,  Fran- 
cis and  Beyer,142  who  demonstrated  the  existence  in  malarial 
blood  of  a  poison  capable  of  reproducing  the  symptoms  of 
the  disease  when  injected  into  the  veins  of  other  men.  The 
details  of  their  experiment  with  tertian  malaria  are  reproduced 
as  follows : 

"Andrez  Mendez  (Case  LXVI),  39  years  old;  born  in  La 
Luz,  Estado  de  Guanajuato ;  never  had  fever  in  his  native  place. 
In  1878  had  yellow  fever  (?)  in  San  Antonio,  Estado  de 
Guanajuato,  with  which  he  says  he  was  sick  about  one  month. 
He  came  to  Vera  Cruz  three  years  ago,  and  has  had  fevers 
five  or  six  times  since.  Present  illness  dates  from  about 
November  3,  but  states  that  he  had  been  troubled  with  mild 
attacks  of  fever  for  a  month,  which  he  describes  as  coming 
on  alternate  days,  but  not  sufficiently  severe  to  keep  him  from 
his  work. 

"The  fever  which  initiated  his  present  sickness  began  with  a 
severe  chill  and  was  followed  by  fever  and  sweat,  and  was 
associated  with  some  nausea  and  vomiting.  He  states  that 
these  paroxysms  were  repeated  daily  until  his  admission  to 
San  Sebastian  Hospital,  November  6,  1903. 

"Blood  examination  showed  that  he  had  a  heavy  infection 
with  tertian  parasites,  and  he  was  immediately  transferred  to 
the  laboratory  of  Working  Party  No.  2,  Yellow  Fever  Insti- 
tute. 

"The  man  was  physically  robust,  but  very  anemic,  mucous 
membranes  particularly  pale,  skin  cold  and  damp. 

"At  about  noon  on  this  date  (November  6)  the  patient  was 
seized  with  a  chill. 

"By  12.30,  half  an  hour  later,  the  rigor  was  very  marked ;  he 


I32  THE    STUDY    OF    MALARIA 

lay  in  bed  with  a  blanket  drawn  over  his  head,  and  was  shak- 
ing violently;  he  could  not  hold  a  thermometer  in  his  mouth 
and  the  pulse  was  taken  with  difficulty.  During  this  time  the 
temperature  was  rapidly  rising,  it  being  now  39.1°  C. 

"At  12.40  blood  was  drawn  from  one  of  the  superficial  veins 
at  the  bend  of  the  elbow.  On  account  of  the  rigor  there  was 
some  difficulty  in  introducing  the  needle.  The  blood  flowed 
freely;  125  cc.  were  quickly  drawn.  It  was  permitted  to  flow 
into  a  porcelain  dish  and  immediately  defibrinated  by  whipping 
with  sterilized  forks.  Clotting  took  place  very  quickly,  so 
that  the  fibrin  was  readily  and  quickry  separated  from  the  fluid. 

"Judging  from  the  size  of  the  clot  and  color,  the  fibrin  had 
enmeshed  a  number  of  corpuscles.  The  defibrinated  fluid 
showed  no  further  tendency  to  clot,  and  on  microscopical 
examination  looked  like  fresh  blood  containing  a  normal  num- 
ber of  corpuscles. 

"To  25  cc.  of  defibrinated  blood  was  added  25  cc.  of  physio- 
logical salt  solution,  and  this  diluted  blood  was  filtered  through 
the  same  Berkefield  filter  in  the  same  manner  as  was  done 
with  the  blood  of  Filomena  Martinez.  This  filter  when  tested 
later,  March  1,  1904,  held  back  Staphylococcus  pyogenes 
aureus. 

"Nine  cc.  of  the  filtrate  were  injected  into  the  right  basilic 
vein  of  Louis  Peredo  as  soon  as  this  amount  could  be  obtained. 
This  injection  took  place  at  1.40  p.  m.  It  only  took  about 
forty  minutes  to  defibrinate  and  filter  the  blood,  which  process 
was  done  as  rapidly  as  possible. 

"Stained  smears  of  the  filtrate  showed  no  morphologic  ele- 
ments.    The  filtrate  had  a  distinct  red  color. 

"As  a  control,  Jose  Ojeira,  at  2  p.  mv  was  given  an  injection 
into  his  left  basilic  vein  of  4  cc.  of  the  unfiltered  mixture.  As 
the  blood  was  diluted  with  equal  parts  of  salt  solution,  he, 
therefore,  received  2  cc.  of  Mendez's  blood. 

"The  unfiltered  mixture  of  defibrinated  blood  and  salt  solu- 
tion, upon  microscopic  examination  shortly  after  Ojeira  re- 
ceived his  injection,  showed  ameboid  tertian  organisms  with 
dancing  pigment. 

"After  drawing  the  blood  from  Mendez  he  continued  to  have 


ETIOLOGY  133 

a  chill,  with  a  severe  rigor  and  chattering  of  the  teeth,  accom- 
panied by  nausea  and  vomiting.  His  temperature  continued 
to  rise  after  the  blood  was  drawn  until  it  reached  40.2°  C. 
The  febrile  period  was  followed  by  drowsiness  and  moisture 
of  the  skin. 

"As  will  be  seen  by  reference  to  the  temperature  chart,  Men- 
dez  was  kept  under  observation  without  quinine,  and  had 
another  typical  malarial  paroxysm  the  next  day.  All  the  evi- 
dence in  his  peripheral  blood,  which  was  examined  frequently, 
pointed  to  a  severe  double  infection  with  the  tertian  parasite. 

"He  was  then  given  quinine,  which  entirely  controlled  the 
disease  and  caused  the  complete  disappearance  of  the  parasite 
from  his  peripheral  blood. 

"The  results  caused  by  the  injection  of  the  blood  of  Andres 
Mendez  into  Peredo  and  Ojeira  follow : 

"Luis  Peredo  (Case  LXIV),  a  volunteer,  aged  25;  born  in 
Jalapa,  State  of  Vera  Cruz,  where  he  has  always  lived.  When 
examined  at  Jalapa,  August  26,  he  was  found  to  be  physically 
sound;  urine  contained  no  albumin;  peripheral  blood  showed 
no  Plasmodium. 

"He  was  brought  to  Vera  Cruz  August  28  and  taken  from 
the  station  directly  to  the  laboratory,  from  which  time  he  was 
kept  constantly  within  a  mosquito-proof  room. 

"On  October  27,  after  having  been  under  daily  observation 
two  months,  during  which  time  he  remained  in  normal  health, 
he  was  injected  with  the  filtered  blood  of  Filomena  Martinez, 
who  at  the  time  was  suffering  with  a  paroxysm  of  malarial 
fever  of  the  estivo-autumnal  type,  his  blood  containing  many 
young  ring-forms  and  crescents. 

"It  will  be  noted  by  reference  to  the  records  of  Filomena 
Martinez  that  the  blood  was  drawn  during  the  time  of  the 
decline  of  the  paroxysm.  It  was  then  allowed  to  clot  in  the 
ice  chest,  the  clear  serum  was  pipetted  off  and  diluted  with 
an  equal  quantity  of  isotonic  salt  solution,  and  this  filtered 
through  a  new  Berkefield  filter. 

"Twenty  cc.  of  the  filtrate,  which  on  account  of  the  dilution 
represented  10  cc.  of  the  blood  serum,  were  injected  into  the 
left  median  basilic  vein  of  Peredo. 


134  THE   STUDY   OF  MALARIA 

"For  further  details  of  the  manner  in  which  the  blood  serum 
was  obtained  and  the  filtration  performed,  see  the  above 
records  of  Filomena  Martinez. 

"Peredo  was  carefully  watched  from  the  hour  he  was  in- 
jected, but  he  remained  in  good  health,  and  no  deviation  from 
the  normal  was  detected. 

"His  temperature  was  taken  every  four  hours  during  the 
night  and  day,  both  before  and  following  the  injection,  as 
will  be  seen  by  the  temperature  chart.  No  symptoms  devel- 
oped. 

"His  blood  was  examined  daily  for  plasmodium,  but  none 
was  found.  The  result  of  this  injection  must,  therefore,  be 
considered  negative. 

"Ten  days  later  he  was  again  injected  with  filtered  malarial 
blood  under  different  circumstances,  and  with  positive  results. 

"At  1.40  p.  mv  November  6,  he  was  given  an  intravenous 
injection  of  the  blood  of  Andres  Mendez,  passed  through  the 
same  Berkefield  filter  as  before.  Mendez  was  suffering  with 
a  double  tertian  infection;  his  blood  was  drawn  during  his 
chill  and  before  the  height  of  the  paroxysm,  as  will  be  seen 
by  reference  to  the  temperature  chart. 

"Thinking  that  allowing  the  blood  to  clot  four  or  five  hours 
in  the  ice  chest  in  order  to  obtain  a  clear  serum  for  filtration 
might  be  too  severe  a  tax  upon  the  vitality  of  the  malarial 
parasite,  we  this  time  defibrinated  the  blood  as  quickly  as 
possible,  diluted  it  as  before  with  an  equal  volume  of  physio- 
logic salt  solution,  and  filtered  it  through  the  same  Berke- 
field filter  in  the  same  manner  as  was  done  with  blood  of 
Filomena  Martinez. 

"As  soon  as  9  cc.  of  the  filtrate  could  be  obtained  it  was  in- 
jected into  the  basilic  vein  of  the  right  arm  of  Louis  Peredo. 
This  injection  took  place  at  1.40  p.  m. 

"About  thirty-five  minutes  after  receiving  the  injection  he 
began  having  chilly  sensations  and  headaches,  and  presently 
went  to  bed,  covering  himself  with  his  blanket  (2.25  p.  m.). 
Five  minutes  later  he  was  having  a  violent  chill,  his  teeth  chat- 
tering so  that  we  could  not  trust  the  thermometer  in  his  mouth. 
The  rigor  of  the  entire  body  was  so  marked  that  there  was 


ETIOLOGY  135 

difficulty  in  taking  the  radial  pulse.  The  face  was  pale,  and 
at  this  time  he  vomited  most  of  the  dinner  he  had  eaten  a 
short  time  before  receiving  the  injection. 

"The  patient  complained  of  headache,  which  he  localized  at 
the  forehead  and  occiput;  says  he  felt  cold  and  had  pains  in 
the  knees.  At  this  time  the  skin  was  dry.  The  chill  lasted 
somewhat  over  half  an  hour. 

"At  3  p.  m.  the  patient  had  transient  chilly  creeps,  very 
slight  rigor. 

"At  3.15  p.  m.  he  said  he  felt  'warm  inside,'  and  all  sense 
of  chilliness  had  disappeared ;  still  his  headache. 

"At  3.25  p.  m.  he  complained  of  marked  pain  in  his  legs. 
'  "At  3.30  p.  m.  he  vomited  the  remainder  of  his  dinner. 

"It  will  be  seen  from  the  temperature  chart  that  during  this 
time  his  temperature  was  rapidly  rising,  and  reached  its  high- 
est point  (38.7°  C. )  at  4  p.  mv  just  two  hours  and  twenty 
minutes  after  receiving  the  injection. 

"The  pains  in  the  knees  and  back  continued,  and  nausea  and 
vomiting  now  became  a  distressing  feature  of  the  paroxysms 
for  the  patient. 

"The  fever  gradually  subsided,  and  reached  normal  at  4.30 
a.  m.  the  next  morning. 

"As  the  fever  subsided  the  skin  became  moist,  the  nausea 
and  pains  gradually  disappeared,  so  that  by  6  p.  m.  the  patient 
was  quiet  and  dozing.  The  entire  paroxysm,  therefore,  ac- 
cording to  the  temperature  record,  lasted  about  eight  hours, 
although  the  patient  was  sleeping  quietly  five  hours  after 
receiving  the  injection. 

"It  is  interesting  to  note  that  this  man  (Pedro)  had  what 
seemed  to  be  a  typical  malarial  paroxysm,  beginning  with  a 
distinct  rigor  associated  with  a  rise  of  temperature  and  fol- 
lowed by  slight  sweating.  It  is  of  particular  interest  to  note 
that  his  paroxysm,  so  far  as  symptoms  were  concerned,  was 
very  much  like  the  paroxysm  from  which  Andres  Mendez 
suffered,  especially  the  nausea  and  vomiting. 

"Pedro  was  kept  under  very  close  scrutiny  until  November 
24,  eighteen  days  following  the  injection,  during  which  time 
he  remained  entirely  normal  and  no  plasmodium  appeared  in 


136  THE   STUDY  OF  MALARIA 

his  peripheral  blood,  which  was  frequently  examined,  as  fol- 
lows: 

"November     6 — 4.30  p.  m.,  8  p.  m.     No  malaria. 
"November     7 — 4.30  a.  m.,  8.30  a.  m.,  12.30  p.  m.,  5  p.  m., 

1 1  p.  m.     No  malaria. 
"November     8 — 7  a.  m.,  i  p.  m.,  6  p.  m.,  9.30  p.  m.  No  malaria. 
"November     9 — 7.30  a.  m.,  1.30  p.  m.     No  malaria. 
"November  10 — 2  a.  m.,  3.30  p.  m.,  8  p.  m.,  five  minutes  each. 

No  malaria. 
"November  11 — 4,  7,   10  a.  m.,  2,  6,   11   p.  m.,  five  minutes 

each.     No  malaria. 
"November  12 — 1.30,6.25  a.m., five  minutes  each.  No  malaria. 
"November  13 — 7  a.  m.,  9.30  p.  m.,  five  minutes  each.     No 

malaria. 
"November  14 — 8  a.m.,  8  p.m.,  five  minutes  each.  No  malaria. 
"November  15 — 8  a.  m.,  8.30  p.  m.,  five  minutes  each.     No 

malaria. 
"November  16 — 7  a.  m.,  9.30  p.  m.,  five  minutes  each.     No 

malaria. 
"November  17 — 8  a.m.,  8  p.m.,  five  minutes  each.  No  malaria. 
"Jose  Ojeira  (Case  XXIII),  a  volunteer  from  Jalapa,  18 
years  old;  he  had  never  lived  on  the  coast,  and  says  that  he 
never  had  fever  of  any  kind.  On  examination  in  Jalapa, 
August  11,  he  was  found  to  be  physically  sound,  of  robust 
physique;  urine  showed  no  albumin,  and  blood  examination 
for  malaria  was  negative. 

"He  was  taken  to  Vera  Cruz  August  13  and  immediately 
transferred  to  a  mosquito-proof  room  in  the  laboratory,  where 
he  was  kept  under  close  observation. 

"On  August  28,  at  9.30  a.  m.,  he  was  bitten  by  four  mosqui- 
toes, two  of  which  had  bitten  Antonio  Leal  (Case  XXXV), 
a  yellow- fever  patient,  fifteen  days  seventeen  hours  previously, 
and  the  other  two  had  bitten  the  same  case  fourteen  days 
twenty-three  hours  previously. 

"The  man  was  kept  under  close  observation  in  a  mosquito- 
proof  room,  but  showed  no  reaction.     There  was  no  rise  of 
temperature,  nor  did  he  present  any  untoward  symptoms. 
"On  October  27,  7  p.  m.,  he  received  intravenously  20  cc.  of 


ETIOLOGY  137 

diluted  blood  serum  of  Filomena  Martinez  (estivo-autumnal 
infection),  passed  through  a  Pasteur-Chamberland  filter  B. 
This  represented  10  cc.  of  blood  serum.  For  details  of  this 
filtration  see  Filomena  Martinez. 

"Ojeira  showed  no  reaction  whatever  as  a  result  of  this 
injection. 

"It  will  be  noted  that  the  blood  of  Martinez  was  drawn  after 
the  height  of  the  paroxysm  and  while  the  temperature  was  on 
the  decline. 

"Martinez  was  suffering  with  a  very  severe  estivo-autumnal 
infection  at  the  time  the  blood  was  taken. 

"Ojeira's  blood  was  examined  several  times  daily, both  before 
and  following  this  experiment,  and  at  no  time  was  anything 
resembling  a  malarial  parasite  seen  in  his  peripheral  blood. 

"On  November  6,  the  patient  having  continued  in  good 
health  since  the  last  experiment  was  used  as  a  control  for  the 
experiment  made  on  Peredo. 

"On  this  date,  at  2  p.  m.,  he  was  given  an  intravenous  injec- 
tion of  4  cc.  of  the  unfiltered,  diluted,  and  defibrinated  blood  of 
Andres  Mendez.  At  the  time  the  blood  was  drawn  from 
Mendez  it  contained  a  heavy  infection  of  double  tertian  mala- 
ria, and  the  blood  was  taken  from  him  during  a  chill  and  before 
the  height  of  his  paroxysm.  It  was  at  once  defibrinated,  diluted 
with  an  equal  volume  of  physiologic  salt  solution  and  filtered 
through  a  Berkefeld  filter.  Nine  cc.  of  the  filtrate  were  given 
intravenously  to  Peredo,  causing  a  malarial  paroxysm  without, 
however,  the  presence  of  the  malarial  parasite,  and  due,  as 
we  believe,  to  the  toxin  (?)  in  the  blood  of  Mendez. 

"Ojeira,  who  received  2  cc.  of  unfiltered  blood  (4  cc.  dilu- 
tion), reacted  within  an  hour,  with  a  slight  rise  of  temperature 
and  nausea,  and  four  days  following  developed  a  typical  mala- 
rial paroxysm,  with  many  tertian  parasites  in  the  peripheral 
blood. 

"There  can  be  no  doubt  that  the  reaction  to  the  2  cc.  of 
defibrinated  blood  injected  into  the  vein  of  Ojeira  caused  a 
slight  paroxysm,  which  it  is  reasonable  to  suppose  was  due 
to  the  same  poison  present  in  the  blood  of  Mendez,  and  which 
also  caused  the  reaction  in  Peredo. 


138  THE   STUDY   OF  MALARIA 

"It  will  be  noticed  that  2  cc.  of  this  blood  caused  but  a 
slight  reaction  in  the  case  of  Ojeira,  while  4.5  cc.  caused  a 
more  marked  reaction,  with  a  rise  of  temperature  to  38.7°  C. 
in  the  case  of  Peredo,  indicating  in  a  very  definite  manner  that 
the  severity  of  the  symptoms  were  directly  due  to  the  quantity 
of  poison  introduced.  Ojeira  did  not  have  a  chill  or  other 
manifestations  of  a  malarial  paroxysm  other  than  a  rise  of 
temperature  and  nausea.  He  vomited  gastric  mucus  several 
times. 

"On  November  10,  the  fourth  day  following  the  injection, 
Ojeira  had  a  typical  malarial  paroxysm,  with  tertian  pafasites 
in  his  peripheral  blood.  He  suffered  with  a  double  infection, 
having  a  chill  every  day,  as  will  be  noticed  by  reference  to 
the  temperature  chart. 

"The  character  of  the  parasites  in  his  blood  and  the  clinical 
course  of  the  disease  resembled  in  all  respects  those  of  Mendez, 
from  whom  the  blood  was  taken.  Both  cases  were  entirely 
controlled  by  quinine." 

The  parasites  of  tertian  and  quartan  infections  develop 
uniformly,  one  generation  at  a  time,  hence  typical  paroxysms 
are  the  rule.  Sometimes,  it  is  true,  sporulating  forms  are  met 
with  between  the  accesses,  but  a  certain  dose  of  toxin  is  neces- 
sary to  excite  a  fit.  The  estivo-autumnal  parasites,  on  the 
other  hand,  do  not  sporulate  so  uniformly,  hence  the  poison  is 
liberated  in  broken  doses  and  typical  paroxysms  are  more  fre- 
quently lacking  and  the  fever  more  continuous  or  irregular. 
If  sporulation  occurred  more  nearly  simultaneously,  as  in  the 
tertian  and  quartan  forms  of  malaria,  it  is  probable  that  the 
sudden  discharge  of  the  more  highly  poisonous  estivo-autumnal 
toxin  would  be  more  often  attended  with  serious  consequences. 
The  uniform  sporulation  of  the  tertian  and  quartan  parasites 
may  be  likened  to  a  body  of  soldiers  firing  by  volleys,  while 
that  of  the  estivo-autumnal  parasites  is  similar  to  soldiers 
firing  at  will. 

The  change  of  type  of  malarial  attacks  has  been  used  as 
an  argument  for  the  unity  of  the  malarial  parasites.  It  is 
well  known,  however,  that  such  occurrences  are  best  explained 
by  a  number  of  different  species.     Quotidian  malarial  parox- 


ETIOLOGY  139 

ysms  due  to  two  generations  of  tertian  organisms  may  become 
tertian  in  character  by  the  destruction  of  one  generation. 
Quotidian  paroxysms  due  to  a  triple  quartan  infection  may 
become  quartan  or  double  quartan  by  the  death  of  two  genera- 
tions or  of  a  single  generation  of  parasites.  On  the  contrary, 
tertian  and  quartan  accesses  may  become  quotidian  by  the 
development  into  activity  of  one  or  two  additional  generations. 

It  is  remarkable  in  multiple  infections  by  different  genera- 
tions of  the  same  species  of  parasite  that  they  almost  always 
sporulate  on  different  days  and  very  often  about  the  same 
time  each  day.  Thus  it  is  very  rare  in  double  tertian  infec- 
tions that  two  paroxysms  should  occur  within  one  day  followed 
by  a  fever-free  day.  This  is  probably  best  explained  by  the 
mode  of  infection.  It  is  known  that  the  malarial  mosquitoes 
feed  almost  solely  at  night  and  usually  only  once  during  the 
night.  If  a  subject  is  inoculated  by  the  mosquito  on  two  suc- 
cessive nights  it  is  obvious  that  the  parasite  would  become 
mature  with  an  interval  of  about  twenty-four  hours  between 
the  generations.  If  inoculation  should  occur  upon  three  or 
more  successive  nights  it  is  probable  that  the  third  and  succeed- 
ing generations  would  sporulate,  after  incubation,  simul- 
taneously with  the  first  and  second.  The  interval  between 
multiple  quartan  infections  may  be  explained  similarly. 

Latency  and  relapses  were  formerly  explained  upon  the 
theory  that  so  long  as  the  parasites  remained  below  a  certain 
level  of  asexual  reproduction  the  disease  was  latent,  and  when 
the  parasites  exceeded  in  number  this  level  a  relapse  occurred. 
Sims  has  estimated  the  greatest  number  of  adult  parasites 
which  the  body  can  endure  without  symptoms  as  about  two 
billions.  It  is  probable  that  brief  periods  of  latency  may  be 
thus  explained,  especially  in  persons  possessing  a  relative  im- 
munity, but  it  is  evident  that  this  is  not  a  common  mode,  par- 
ticularly of  relapses  at  long  intervals,  since  the  asexual  cycle 
is  known  to  wear  out  spontaneously  after  certain  periods. 
These  relapses  at  long  intervals  can  be  explained  by  partheno- 
genesis alone.  After  the  schizonts  have  perished,  while  the 
microgametocytes  do  not  persist  long,  the  macrogametes  re- 
main for  indefinite  periods.    They  may  sporulate  more  or  less 


140  THE   STUDY  OF   MALARIA 

regularly,  causing  paroxysms  at  intervals  of  about  a  week,  or 
multiples  thereof,  or  may  lie  dormant  until  aroused  into  repro- 
ductive activity  by  exposure  or  dietary  or  other  excesses.  It 
is  highly  probable  that  the  parthenogenetic  cycle  of  reproduc- 
tion is  conducted  almost  altogether  in  the  visceral  circulation, 
particularly  in  the  spleen.  As  evidence  of  this  may  be  cited 
the  outbreaks  of  malaria  following  cold  douching,  electrical 
stimulation,  and  trauma  of  the  splenic  region. 

The  anemia  of  malaria  depends  upon  three  factors:  i,  the 
mechanical  destruction  of  cells  by  the  parasites;  2,  the  effect 
of  toxins,  and,  3,  the  activity  of  the  blood-making  organs. 
Liberated  hemoglobin  is  transformed  by  the  liver  into  bile 
pigment.  When  the  hemoglobin  is  liberated  too  fast  for  the 
liver  to  utilize,  hemoglobinemia  results,  and  hemosiderin  is 
precipitated  from  the  blood.  The  increased  activity  of  the 
liver  results  in  polycholia  and  icterus.  It  is  probable  that  jaun- 
dice is  due  also  when  the  liver  capacity  is  overtaxed  to  hemo- 
globinemia. When  hemoglobinemia  exceeds  a  certain  limit  the 
hemoglobin  is  excreted  by  the  kidneys,  resulting  in  hemo- 
globinuria. 

Splenic  enlargement  is  effected  through  hyperemia,  deposi- 
tion of  detritus  of  destroyed  erythrocytes,  accumulation  of 
parasites,  and  hyperplasia  of  the  pulp. 

Spontaneous  cure  is  probably  due  to  the  natural  weakening 
of  the  reproductive  powers  of  the  parasite,  a  phenomenon 
occurring  in  strains  throughout  the  vegetable  and  animal  king- 
doms, and  possibly  also  to  the  influence  of  an  antitoxin. 
Phagocytosis  plays,  in  the  opinion  of  the  writer,  a  much  less 
prominent  role  than  is  usually  attributed  to  it.  It  is  probable 
that  this  function  is  exercised  mainly  after  the  parasites  have 
lost  vitality  from  other  causes. 

ETIOLOGY  OF  PERNICIOUS  MALARIA 
Pernicious  malaria  is  that  form  of  malaria  so  acute  that, 
independently  of  complications,  life  is  endangered  in  a  few 
hours  or  a  few  days.  This  gravity  may  be  due  to  the  intensi- 
fication of  ordinary  malarial  symptoms  or  to  the  advent  of 
unusual  ones.     It  should  be  clearlv  understood  that  pernicious 


ETIOLOGY  I41 

fever  is  not  a  pathologic  entity,  but  is  a  form  of  malaria, 
from  the  simple  modes  of  which  it  sometimes  differs  only  in 
degree. 

In  America  pernicious  malaria  is  rarely  seen  in  the  adult 
negro,  by  far  the  greater  number  of  cases  occurring  in  this 
race  being  in  children  under  ten.  This  coincides  with  the  expe- 
rience of  those  who  have  practised  among  the  blacks  of  Africa. 
It  is  not  common  among  the  natives  of  Algeria  or  Arabia. 
The  natives  of  India  are  not  immune,  and  the  Chinese  are 
very  susceptible.  Koch143  relates  that  of  273  Chinese  imported 
from  Hong  Kong  to  Stephansort  in  1898,  125  died  within  the 
course  of  a  year,  mostly  of  malaria. 

More  cases  occur  in  males  than  in  females.  This  is  not 
because  of  greater  susceptibility,  but  on  account  of  more  fre- 
quent exposure  of  the  male  sex.  Crespin144  believes  that  preg- 
nancy may  render  pernicious  attacks  that  have  no  grave  tenden- 
cies. Bell145  reports  a  case  of  comatose  malaria  in  a  Chinese 
woman  who  was  eight  months  pregnant.  Premature  delivery 
occurred  on  the  second  day,  the  child  being  dead,  and  the 
mother  died  on  the  seventh  day.  Dos  Santos146  describes  a 
case  of  algid  malaria  in  a  woman,  age  twenty-seven,  six  months 
pregnant.  Abortion  occurred  thirty-six  hours  after  onset  of 
the  attack.  The  placenta  was  enormous.  The  woman  recov- 
ered. Ten  months  later  the  same  woman  was  assailed  with  a 
similar  attack  while  six  months  pregnant.  She  aborted  again 
and  made  a  good  recovery. 

Children  are  prone  to  pernicious  attacks,  especially  of  the 
cerebral  type.  Sixty-nine  cases  observed  by  Martirano147  give 
the  following  age  distribution: 

Under  nine  months 

One    year    old * 9 

Two   years   old R 

From  three  to  four  years ° 

From  five  to  ten  years 5 

From  ten  to  thirty  years 5 

From  thirty  to  seventy  years -_£4 

69 

In  another  series  of  25  under  Martirano's147  care,  13  were 
children  and  12  were  adults.     In  31  cases  of  Tanzarella,84  19 


142  THE   STUDY   OF   MALARIA 

were  under  ten  years  of  age  and  12  older.  Caccini's147  99 
cases  show  an  unusually  small  per  cent,  in  children,  only  14 
cases  occurring  in  children  under  ten  years  of  age. 

The  convulsive  form  is  relatively  frequent  in  children  living 
in  highly  malarial  countries.  According  to  Thornhill,148  in 
Ceylon  during  1896,  40.52  per  cent,  of  children  dying  under 
one  year  of  age  died  of  convulsions,  most  of  which  were  due 
to  malaria.  Speaking  of  pernicious  malaria  in  British  Malaya, 
Travers  says :  "The  infant  mortality  on  some  estates,  where 
the  coolies  suffer  much  from  fever,  is  terribly  high.  I  know 
of  one  estate  (since  abandoned)  on  which  a  large  Tamil  labor 
force  was  employed  where  all  the  infants  died.  The  manager 
offered  a  reward  for  the  first  child  successfully  reared  on  the 
estate,  but  that  reward,  I  believe,  was  never  claimed." 

Convulsive  pernicious  is  apt  to  attack  children  with  nervous 
predisposition,  either  hereditary  or  acquired.  It  is  rare  in 
adults,  though  Maurel,  Reynaud,  and  Duberge  have  seen  such 
cases.86    The  aged  are  more  susceptible  to  comatose  attacks. 

In  the  Southern  States  pernicious  malaria  is  more  prevalent 
at  the  height  of  the  malarial  seasons,  especially  in  July,  August, 
and  September.  In  Southern  Europe  and  in  Algiers  the  season 
is  said  to  be  from  July  to  November.  In  Greece  cases  appear 
in  July  are  most  frequent  in  autumn,  and  are  rare  in  winter. 
In  India  it  is  at  the  acme  of  the  malarial  season  that  these 
attacks  occur. 

Eleven  hundred  and  one  cases  from  various  sources  are  dis- 
tributed as  follows : 

Candi,"'      Marti-         Tanza-     Billett  i«    Caccmi,i«     rano!»«  Tnt  . 

Cochin      rano,™        re  la,"  My.'  Ital'y  Total. 

Chma.         Italy.  Italy.  B  (1901). 


I  .  .  .  .  . .  40 

43 
80 

1  . .  . .  . .  100 


1  1  ..  ..  112 

2  1  1  . .  130 


January    39 

February    43 

March  80 

April   99 

May no 

June  126 

July   115              1              8              2              4              5              13S 

August    79              5            10            II            18            25              148 

September   54            I0              3            *3              7            21              108 

October    52              5              2            12            12              7                00 

November    47              4              3             •  •             i2              6                72 

December  36            . .            ^            ^            _2            _5                43 

Total  "880            25            31            40            55            69            hoi 


ETIOLOGY  143 

The  influence  of  inundations  on  the  etiology  of  pernicious 
fever  is  well  recognized.  In  1826  Johnson16  wrote :  "There  is 
no  unmixed  good  in  this  world.  The  inundations  of  the  Nile 
and  the  Ganges,  while  they  scatter  fertility  over  the  valley  of 
Egypt  and  the  plains  of  Bengal,  sow  with  a  liberal  hand  at  the 
same  time  the  seeds  of  dreadful  diseases."  This  is  in  all  proba- 
bility true  of  the  Mississippi  and  other  large  rivers  of  our 
country.  In  1854  Frerichs  recorded  an  epidemic  of  pernicious 
malaria  following  an  overflow  of  the  Oder  where  there  had 
previously  been  only  mild  cases  of  malaria. 

The  length  of  residence  in  a  malarial  region  is  probably 
not  an  important  factor  in  the  etiology  of  the  affection.  While 
Sims152  and  others  believe  that  it  occurs  mainly  in  the  early 
period  of  residence,  most  of  Maurel's75  cases  were  in  persons 
who  had  been  in  the  colony  a  long  time.  Plehn5  mentions  the 
case  of  a  young  physician  who  died  of  pernicious  malaria  six 
days  after  arrival  at  Banana. 

MaureF  states  that  outbreaks  of  pernicious  malaria  may 
occur  several  years  after  return  to  France  from  the  tropics, 
and  without  new  infection.  During  and  shortly  after  the  war 
with  Spain  numerous  cases  which  were  infected  in  Cuba  and 
the  Philippines  were  treated  in  American  hospitals.  Rees15S 
records  the  case  of  a  man  who  had  spent  only  five  days  in  an 
endemic  region  and  developed  comatose  malaria  with  fatal 
termination  in  a  few  weeks  after  his  return  to  London.  Satter- 
lee,154  Hall,155  Neer,158  and  others  have  observed  similar  cases 
in  America.  In  the  majority  of  such  cases  the  outbreak  occurs 
within  a  few  weeks  after  leaving  the  endemic  area. 

Occupations  which  subject  not  only  to  malarial  infection, 
but  to  hardships  and  exposure,  especially  to  the  sun,  predispose 
to  pernicious  attacks.  Manson59  cites  the  case  of  Hong  Kong, 
formerly  healthy  enough,  but  when  barracks  and  houses  were 
being  built  and  roads  laid  out  the  soldiers  died  by  the  hundred 
of  pernicious  fevers.  Homem157  asserts  that  these  cases  occur 
in  Rio  de  Janeiro,  particularly  when  the  sewerage,  gas,  and 
water  companies  are  making  deep  and  extensive  excavations  in 
the  more  central  streets  of  the  city.  Early  in  the  last  century, 
when  the  marsh  of  Chartreuse,  near  Bordeaux,  was  drained, 


144  THE   STUDY   OF   MALARIA 

an  epidemic  of  severe  malaria  prevailed,  and  in  1805  12,000 
people  were  stricken,  of  whom  3,000  died  in  five  months. 

As  it  is  especially  in  the  laboring  and  poorer  classes  that 
primary  infections  do  not  receive  adequate  treatment,  it  is 
largely  in  this  class  that  pernicious  attacks  are  found. 

Pernicious  attacks  may  be  first  attacks  or  they  may  occur 
in  cachectics,  but  it  is  chiefly  between  these  extremes  that  most 
attacks  originate,  namely,  in  those  having  had  previous  attacks 
of  malaria,  but  who  are  not  saturated  to  the  degree  of  cachexia. 
Laveran,1  Marchiafava  and  Bignami,22  and  Sambon9  have 
never  seen  pernicious  attacks  without  previous  malaria. 
Ruge,158  however,  states  that  such  cases  are  not  uncommon  in 
India  and  both  the  east  and  west  coasts  of  Africa.  Colin  and 
Antoniades  have  observed  like  cases.159  Wurtz  and  Thiroux160 
say  that  the  typhoid  form  is  most  often  a  fever  of  first  inva- 
sion. Roux161  knows  of  numerous  examples  of  pernicious 
fever  as  the  first  manifestation  of  malaria.  Mannaberg141^ 
asserts  that  it  may  attack  those  who  have  never  before  suffered 
from  malaria,  as  well  as  those  who  have  undergone  repeated 
attacks.  Horaem157  says  that  in  many  cases  the  pernicious 
paroxysm  is  preceded  by  simple  ones;  in  others  the  patient  is 
attacked  while  in  perfect  health.  It  is  the  comatose  form  that 
is  most  frequently  seen  in  those  who  have  not  previously  been 
attacked  with  malaria.  Crespin's144  experience  is  that  the  at- 
tacks are  exceptional  in  chronic  malarials.  Smart76  records  it 
that  during  the  Civil  War  pernicious  attacks  occurred  not  only 
in  persons  who  were  for  the  first  time  exposed  to  a  highly 
malarial  atmosphere,  but  also  among  those  who  had  suffered 
more  or  less  from  the  malarial  influence  before  the  superven- 
tion of  the  congestive  seizure.  In  50  cases  observed  by  Carda- 
matis  and  Diamessis35  only  one  developed  as  a  primary  attack 
Most  of  the  algid  and  comatose  cases  of  Maurel  were  in  sub- 
jects of  chronic  malaria.  Thayer98  and  Craig70  say  that  it  is 
customary  for  malarial  paroxysms  to  precede.  Schellong92 
agrees  with  Martin  that  pernicious  fever  attacks  persons  al- 
ready rendered  anemic  from  malaria. 

While  it  is  probably  true  that  in  the  majority  of  instances 
typical  paroxysms  precede  pernicious  attacks,  it  is  of  the  utmost 


ETIOLOGY  145 

importance  to  bear  in  mind  that  the  latter  may  be  manifesta- 
tions of  first  invasion.  "If  there  are  cases  of  pernicious  fever, 
in  which  the  patient  has  been  attacked  previously  by  paroxysms 
of  simple,  well-marked  or  masked  intermittent,  there  are  also 
cases,  unhappily  numerous,  in  which  it  is  the  pernicious  attack 
that  opens  the  scene,  where  the  subject,  in  the  enjoyment  of 
the  most  flourishing  health,  is  treacherously  assailed  by  the 
terrible  enemy  without  the  least  signal  to  warn  of  the  enormous 
peril  awaiting  him. ' '     ( Homem. ) 

Pernicious  malaria  is  almost  as  varied  in  pathogenesis  as 
it  is  in  manifestations.  Not  only  are  its  several  forms  asso- 
ciated with  unlike  conditions,  but  for  the  explanation  of  some 
the  presence  of  several  different  factors  is  necessary.  Thus 
comatose  malaria  may  be  associated  with  at  least  two  different 
forms  of  the  parasite;  the  peripheral  blood  may  show  very 
great  numbers  of  these  parasites  or  they  may  be  scanty ;  in  the 
brain  they  may  be  found  in  hordes,  even  to  the  occlusion  of 
small  vessels,  or  they  may  be  entirely  absent. 

As  may  be  inferred,  no  one  etiologic  element  can  account 
for  all  cases,  even  of  the  same  type.  Probably  the  only  essen- 
tially common  factor  is  the  presence  of  the  malarial  parasite, 
the  manifestations  of  which  run  the  gamut  from  the  mildest 
intermittent  to  the  profoundest  cachexia,  from  the  most  art- 
fully masked  to  the  deadliest  pernicious. 

Until  comparatively  recently  it  was  believed  that  infections 
with  the  so-called  benign  organisms  never  gave  rise  to  perni- 
cious symptoms.  Celli80  states  that  the  tertian  and  quartan 
parasites  never  cause  pernicious  fevers.  Marchiafava  and  Big- 
nami162  say  that  there  is  no  instance  on  record  of  a  malignant 
fever  following  tertian  and  quartan  infections,  and  that  no 
autopsy  has  ever  been  made  in  connection  with  a  malignant 
spring  tertian  or  quartan.  Mannaberg,141  Van  der  Scheer,16; 
and  Maurer135  believe  that  only  the  estivo-autumnal  parasites 
have  a  role  in  the  production  of  the  pernicious  fevers.  Thayer, 
in  his  "Lectures  on  the  Malarial  Fevers,"  says  that  he  never 
heard  of  a  pernicious  paroxysm  occurring  in  tertian  or  quartan 
infections,  with  the  exception  of  the  case  of  French. 

While  the  vast  majority  of  cases  of  pernicious  malaria  are 
10 


146  THE   STUDY   OF   MALARIA 

due  to  the  infection  with  the  tropical  parasites,  it  cannot  now 
be  maintained  that  tertian  and  quartan  infections  are  not  occa- 
sionally accompanied  by  perniciousness.  Craig164  says  that  any 
of  the  malarial  parasites  may  cause  pernicious  infections,  lead- 
ing to  death.  Crespin165  informs  us  that  it  is  not  rare  to  find 
on  examination  tertian  and  quartan  parasites  in  these  cases. 
Billet151  found  the  large  tertian  in  6  of  40  cases  of  typhoid 
pernicious.  Ziemann96  observed  a  case  of  pernicious  malaria 
due  to  the  benign  tertian.  ThirouxS6  found  this  parasite  in 
a  case  of  convulsive  pernicious  in  a  mulatto  infant.  Ewing,27 
in  64  cases  of  the  cerebral  type  of  pernicious,  found  the  large 
tertian  parasite  alone  in  5.  French166  reports  a  case  of  coma- 
tose malaria  in  a  man,  aged  twenty-one,  whose  blood  harbored 
the  tertian  parasite.  Hunt167  observed  a  case  of  common  tertian 
complicated  by  alarming  hematemesis  in  a  boy  aged  eleven. 
McElroy168  had  a  case  of  comatose  pernicious  due  to  tertian 
infection  in  a  negro  male,  aged  thirty.  Ficucci169  records  a 
case  with  a  pernicious  meningo-cerebellar  syndrome  due  to 
tertian  parasites.  Fenner170  gives  the  history  of  a  case  of  the 
comatose  type  in  an  adult;  the  blood  examinations  showed 
crescents  and  large  tertian  forms. 

Craig1*64  makes  the  assertion  that  quartan  infections  are 
more  apt  to  become  pernicious  than  tertian.  The  writer,  how- 
ever, agrees  with  Davidson,66  who  says  that  pernicious  symp- 
toms occur  more  rarely  in  connection  with  the  quartan  infec- 
tions than  with  simple  tertian.  The  reasons  for  this  are  proba- 
bly the  relative  rarity  of  quartan  fever  and  the  more  even 
distribution  of  parasites  throughout  the  circulation,  there  being 
slight  tendency  to  form  accumulations. 

It  is  not  yet  known  with  certainty  which  variety  of  the 
estivo-autumnal  parasite  gives  rise  most  frequently  to  perni- 
ciousness. Marchiafava  and  Bignami162  and  Mannaberg141 
hold  that  the  tertian  estivo-autumnal  infections  are  the  most 
dangerous,  only  a  few  cases  showing  the  quotidian.  Craig,70 
however,  found  the  quotidian  parasite  most  often  in  cases  in- 
fected in  Cuba  and  in  the  Philippines.  This  was  also  the  expe- 
rience of  Wright38  in  British  Malaya,  who  found  the  pigmented 


ETIOLOGY  147 

quotidian  parasite  most  frequently  associated  with  the  cerebral 
and  gastro-intestinal  types  of  pernicious  malaria. 

The  part  played  by  the  crescents  in  the  pathogenesis  of  per- 
nicious paroxysms  is  worthy  of  brief  consideration.  Marchia- 
fava  and  Bignami,22  Celli,80  Mannaberg,141  A.  Plehn,171 
Koch,  172  Manson,59  Thayer,98  and  others  believe  that  this  form 
of  the  organism  is  non-pyrogenic.  Ewing,130  however,  holds, 
with  Laveran,  that  it  is  by  no  means  certain  that  the  formation 
and  development  of  the  crescents  are  entirely  innocuous  to  the 
patient.  Ewing,  doubtless  in  part,  bases  this  opinion  on  the 
finding  of  crescents  alone  in  33  of  64  cases  of  cerebral  perni- 
cious.27 Whether  the  blood  examined  in  these  cases  was  per- 
ipheral or  visceral  is  not  stated,  but  as  only  three  were  fatal 
it  may  fairly  be  assumed  that  in  most  instances  at  least  it  was. 
peripheral.  That  the  crescentic  form  of  the  parasite  has  an 
intimate  relation  to  the  production  of  the  pernicious  fevers  is 
improbable,  for  the  following  reasons :  First,  crescents  alone 
may  be  found  in  the  peripheral  blood,  and  intense  localization 
of  active  forms  be  present  in  the  brain  or  other  viscera.  The 
number  of  parasites  in  the  superficial  circulation  is  not  a  reliable 
guide  to  the  severity  of  the  attack.  Of  Ewing's  64  cerebral 
cases  no  parasites  were  identified  in  11,  and  in  many  of  his 
33  cases  in  which  crescents  alone  were  found  the  search  was 
successful  only  after  one  and  two  hours.  Second,  crescents 
are  rarely,  if  ever,  present  in  the  parasitic  localizations  and 
thrombi  frequently  observed  in  pernicious  cases. 

Of  the  pathogenetic  factors  which  excite  perniciousness  the 
following  are  to  be  regarded  as  the  most  important  and  ap- 
proximately of  relatively  equal  importance: 

1.  An  excessive  number  of  parasites. 

2.  Localizations  of  parasites. 

3.  Toxins. 

4.  Individual  predisposition  and  external  etiologic  influences. 
Number  of  Parasites. — Golgi's  law,  that  the  number  of 

parasites  determines  the  severity  of  the  attack,  has  been  gen- 
erally accepted.  Cases  in  which  the  parasites  are  in  very  great 
numbers  in  the  peripheral  blood  are  usually  accompanied  by 
coma. 


14-8  THE   STUDY   OF  MALARIA 

We  have  no  means  of  estimating  even  approximately  the 
total  number  of  malarial  parasites  in  the  body  of  a  malarial 
patient,  as  the  distribution  of  the  former  varies  within  the 
widest  limits.  They  may  be  numerous  in  the  peripheral  and 
visceral  circulation  generally;  they  may  be  scanty  or  absent  in 
the  peripheral  circulation  and  numerous  in  most  of  the  viscera; 
or  they  may  exist  in  moderate  numbers  or  be  absent  except  in 
certain  areas  where  they  may  be  intensively  localized.  That 
the  parasites  are  abundant,  either  absolutely  in  the  body  as  a 
whole  or  relatively  in  certain  areas,  probably  holds  good  in 
a  great  majority  of  the  cases,  though,  as  Celli80  states,  we 
cannot  always  attribute  perniciousness  to  the  large  number 
of  parasitic  forms.  Marchiafava  and  Bignami22  call  attention 
to  certain  grave  cases  of  comatose,  convulsive,  delirious  or 
mixed  pernicious,  in  which  from  beginning  to  end  and  even 
at  autopsy  very  few  parasites  are  found.  Mannaberg14L  says : 
"From  the  general  impression  which  I  have  obtained  naturally 
from  the  peripheral  blood,  the  number  in  malignant  fevers  is 
perhaps  larger,  yet  the  difference  scarcely  seems  so  decided  as 
to  make  this  factor  alone  responsible  for  the  perniciousness." 

As  applied  to  the  number  of  parasites  in  the  peripheral  blood, 
Golgi's  rule  is  applicable  only  in  a  very  general  sense.  Bacelli173 
says  that  fatal  cases  of  malaria  occur  in  which  there  cannot 
be  found  any  known  form  of  the  parasite. 

Ziemann48  states  that  the  number  of  parasites  in  the  per- 
ipheral blood  is  not  always  in  direct  relation  to  the  severity 
of  the  attack.  Crespin144  acknowledges  that  he  had  difficulty 
in  finding  the  parasites,  which  were  always  scanty  in  these 
cases.  He  gives  the  details  of  a  case  in  which  there  were 
neither  parasites  nor  pigment  in  the  peripheral  blood,  but  they 
were  numerous  in  the  vessels  of  certain  viscera.  This  writer 
quotes  Nocht  as  saying:  "In  pernicious  attacks  the  hematozoa 
are  notiound  in  the  peripheral  blood,  but  only  in  the  viscera." 
Moore25  says :  "I  have  often  seen  cases  where  the  symptoms 
in  no  wise  seemed  commensurate  with  the  number  of  parasites 
observed  in  the  specimen  of  blood."  According  to  Kendall,30 
there  may  be  only  a  few  parasites  in  the  peripheral  circulation, 
or  it  may  be  even  impossible  to  find  them.     Mannaberg141  states 


ETIOLOGY  149 

that  it  sometimes  happens  that  the  peripheral  blood  is  very- 
poor  in  parasites.  Marchiafava  and  Bignami22  note  the  fact 
that  the  contradiction  found  so  often  during  life  between  the 
number  of  the  parasites  and  the  gravity  of  the  disease  dis- 
appears when  an  autopsy  allows  of  an  examination  of  all  the 
organs.  Craig70  asserts  "that  the  number  of  the  parasites 
found  in  the  peripheral  blood  is  not  always  a  criterion  as  to 
the  perniciousness,  as  one  of  the  most  rapidly  fatal  cases  I 
have  ever  observed  showed  but  few  parasites  in  the  peripheral 
blood."  To  quote  Barker  :17i  "In  the  estivo-autumnal  infections 
the  number  of  organisms  circulating  in  the  peripheral  parts 
affords,  as  a  rule,  very  insufficient  data  upon  which  to  base 
an  idea  of  the  severity  of  the  infection."  Thayer98  says  that 
there  may  be  very  few  parasites  in  the  peripheral  circulation. 
He  mentions  a  fatal  case  of  the  comatose  variety  showing  no 
active  parasites  in  the  peripheral  blood  and  only  a  few  ovoids 
and  crescents  after  a  careful  search  of  the  blood,  obtained  by 
puncture  of  the  spleen.  Marchoux105  reported  3  cases  of  perni- 
cious malaria  in  which  the  parasites  were  very  scanty  in  the 
peripheral  circulation.  Zeri175  records  4  cases  of  pernicious 
fever  in  all  of  which  the  parasites  were  few  in  number.  Bloom- 
bergh  and  Coffin176  treated  a  case  ending  fatally  in  which  no 
parasites  could  be  found  until  forty-eight  hours  after  onset, 
notwithstanding  repeated  examinations.  In  7  cases  in  which 
Fenner170  examined  the  blood  no  parasites  were  found  in  5. 
Ewing's27  1 1  cases  of  the  comatose  form,  in  which  no  parasites 
were  identified,  have  been  mentioned.  The  writer  has  observed 
1  case  of  severe  comatose  malaria  in  a  boy,  aged  twelve,  in 
whose  peripheral  blood  the  parasites  were  scanty. 

On  the  other  hand,  the  superficial  circulation  may  be  teem- 
ing with  parasites,  while  the  patient  experiences  only  a  mild 
attack.  Thus  A.  Plehn"  gives  the  histories  of  2  cases  in  which 
the  symptoms  were  slight  though  the  peripheral  blood  showed 
as  many  as  thirty-five  and  forty-six  tropic  parasites,  respec- 
tively, to  each  field  of  the  microscope. 

It  is  highly  probable  that  an  enormous  number  of  parasites, 
equally  distributed,  depends  for  their  power  to  elicit  pernicious 
symptoms  upon  the  increased  quantity  of  toxin  elaborated. 


150  THE  STUDY  OF  MALARIA 

Localizations  of  Parasites. — Accumulations  of  parasites  in 
the  brain  were  first  described  by  Planer  (1854),  and  by  Fre- 
richs  (1861)  ;  those  in  the  liver  by  Guarnieri  (1867).  More 
recently  the  minute  observations  of  Marchiafava  and  Bignami, 
Dock,  Barker  and  Ewing  have  taught  us  that  pernicious  mala- 
ria, in  many  of  its  varied  manifestations,  is  dependent  on 
these  localizations  in  one  or  more  of  a  multiplicity  of  localities. 
Localizations  in  the  brain  have  been  found  associated  with  a 
wide  variety  of  cerebral  symptoms;  in  the  mucosa  of  the  ali- 
mentary tract,  the  gastro-intestinal  symptoms,  and  typical  algid 
attacks;  in  the  heart,  with  cardiac  symptoms;  in  the  medulla, 
with  bulbar  paralysis;  in  the  retina,  with  amblyopia;  in  the 
pancreas,  with  hemorrhagic  pancreatitis,  etc.  In  proportion  to 
the  amount  of  damage  sustained  by  the  kidneys  in  malaria 
there  is  less  tendency  for  parasites  in  pernicious  attacks  to  accu- 
mulate in  these  organs  than  in  any  other  of  the  body.  The 
most  carefully  studied  case  of  this  condition  is  that  of  Ewing.177 

These  localizations  consist,  in  the  main,  of  parasite-infected 
red  blood-cells.  There  may  be,  however,  pigmented  leucocytes 
and  free  parasites  and  pigment.  The  parasites  in  each  particu- 
lar case  may  be  of  the  same  or  of  different  stages  of  develop- 
ment. The  pigmented  and  sporulating  forms  are  probably 
oftenest  seen,  but  the  earlier  phases  are  frequently  observed. 
It  would  seem  reasonable  that  the  crescents,  on  account  of  their 
size,  would  frequently  form  an  important  element  in  these  accu- 
mulations of  parasites,  but  such  does  not  appear  to  be  the  case. 

The  cause  of  the  parasitic  concentrations  is  problematical. 
It  cannot  be  due  to  the  size,  weight  or  loss  of  elasticity  of  the 
infected  cells,  for,  as  Mannaberg141  states,  the  benign  parasite 
would  be  more  apt  to  form  thrombi  if  this  were  the  cause. 
Kelsch  and  Kiener178  and  others  have  observed  endothelial 
swellings  in  the  small  cerebral  vessels,  with  consequent  constric- 
tion of  calibre,  but  whether  this  is  a  cause  or  an  effect  cannot 
be  said.  Vasomotor  disturbances  and  phagocytosis  have  also 
been  invoked  in  explanation.  The  most  probable  theory  is  that 
of  Mannaberg,141  who  attributes  the  condition  to  a  sort  of 
agglutination  or  adhesiveness  that  holds  the  erythrocytes  to 
the  vessel  walls. 


ETIOLOGY  151 

The  symptoms  present  in  cases  in  which,  on  post-mortem 
examination,  localizations  of  parasites  are  demonstrated  are  not 
always  referable  to  these  aggregations  alone,  since  changes  are 
frequently  observed  which  are  secondary  to  parasitic  throm- 
bosis, and  may  outweigh  the  latter  in  pathogenic  importance. 

The  most  conspicuous  of  these  changes  are  perivascular  exu- 
dation, hemorrhage  and  necrosis.  The  hemorrhages  are  usu- 
ally punctate,  but  Blanc179  and  Ziemann48  report  large  cerebral 
clots. 

This  propensity  of  the  parasites  in  pernicious  fever  to  con- 
gregate undoubtedly  explains  the  course  of  many  cases,  but 
by  no  means  all.  Fatal  cases  of  comatose  malaria  have  been 
observed  with  no  parasites  at  all  in  the  brain.  Ford180  reports 
a  case  with  serious  pulmonary  symptoms  in  which  the  parasites 
were  no  more  numerous  in  the  lung  than  in  the  general  circu- 
lation. "The  severity  of  the  renal  lesion,  with  the  absence  of 
parasites  in  the  renal  vessels,  also  requires  mention."181 

It  is  not  known  whether  parasitic  thrombi  may  exist  without 
producing  symptoms.  Frerichs,96  who  frequently  observed 
thrombotic  occlusions  of  the  cerebral  vessels,  insisted  that  too 
much  stress  should  not  be  laid  on  them  on  account  of  the  rich 
collateral  circulation.  He  likewise  affirmed  that  he  had  more 
than  once  seen  markedly  pigmented  brains  without  cerebral 
symptoms  during  life. 

Based  on  a  case  in  which  the  patient  was  suddenly  attacked 
with  transient  coma  three  times  in  five  days,  Ewing181  believes 
that  the  embolic  processes  are  factors  in  some  instances. 

This  is  the  most  probable  explanation  of  these  cases. 

Toxins. — The  evidence  of  the  existence  of  a  toxin  in  malaria 
has  been  detailed  above. 

Individual  Predisposition  and  External  Etiologic  Influ- 
ences.— "We  ought,  then,  in  cases  of  pernicious  fever,  to  seek 
in  the  conditions  of  the  ground,  whose  quality  is  so  different, 
and  not  in  the  quantity  of  the  seed,  the  reason  which  shall  ex- 
plain to  us  the  gravity  of  the  disease."157 

The  quality  of  the  soil,  in  the  sense  so  aptly  employed  by 
Homem,  as  a  factor  in  the  pathogenesis  of  pernicious  malaria 
has  probably  not  received  the  attention  it  deserves.    This  influ- 


152  THE   STUDY   OF  MALARIA 

ence,  in  many  instances,  doubtless  not  only  induces  the  attack, 
but  determines  its  type.  Organs  or  systems  enfeebled  by  ante- 
cedent ailments  are  apt  to  play  the  title  role  in  the  pernicious 
tragedy.  Thus  algid  and  choleraic  attacks  may  be  associated 
with  a  history  of  intestinal  catarrh;  the  comatose  and  delirious 
cases,  with  a  history  of  abuse  of  alcohol;  the  convulsive  with 
epilepsy,  etc.  It  is  not  improbable  that  some  cases  of  dysenteric, 
cardialgic,  syncopal,  tetanic,  cataleptic,  paralytic,  pneumonic, 
pleuritic,  gastralgic,  and  other  forms  described  by  the  older 
writers  may  be  similarly  explained.  Mercier1S2  goes  so  far  as 
to  say  that  all  pernicious  attacks  are  merely  visceral  complica- 
tions. 

Malarial  subjects  who  are  much  exposed  to  the  heat  of  the 
sun  are  liable  to  be  stricken  with  pernicious  fever,  especially  of 
the  cerebral  type.  This  danger  is  enhanced  if  to  the  solar  heat 
are  added  fatigue,  deficient  or  improper  food,  or  other  hard- 
ships. Certain  psychic  states  have  causative  significance. 
Hertz183  states  that  he  has  seen  the  localization  of  pernicious 
symptoms  determined  by  injuries  of  the  skull  through  a  fall 
or  a  blow. 

In  addition  to  the  four  principal  factors  enumerated,  con- 
gestion of  viscera  and  parasitic  obstruction  of  the  hepatic  capil- 
laries have  been  regarded  as  important.  It  is  probable  that  they 
have  little  influence. 

A  feeble  phagocytic  activity  was  considered  by  Golgi  as 
predisposing  to  pernicious  attacks.  In  the  present  state  of  our 
knowledge  it  is  impossible  to  define  the  relation  of  this  func- 
tion to  perniciousness. 

A  consideration  of  the  relative  frequency  with  which  the 
several  factors  are  concerned  in  the  pathogenesis  of  the  various 
forms  of  pernicious  malaria  will  necessarily  be  brief.  In  the 
comatose  variety  any  of  the  four  chief  agents  may  take  part; 
idiosyncrasy  and  external  influences  may  unite  with  any  of  the 
other  factors;  an  extraordinary  number  of  parasites  in  the 
general  circulation,  without  accumulations  in  the  brain,  is  pro- 
ductive of  coma  probably  because  of  the  toxin.  Ewing181  says 
that  the  majority  of  cases  of  comatose  malaria  coming  to 
autopsy  do  not  show  a  massing  of  parasites  in  the  brain.     He 


ETIOLOGY  153 

attributes  these  cases  to  general  toxemia.  However,  a  study 
of  the  autopsy  records  of  Marchiafava  and  Bignami162  shows 
that  in  a  great  majority  of  their  fatal  comatose  cases  the  para- 
sites were  markedly  localized  in  the  brain.  Davidson06  and 
Ruge158  believe  that  almost  always  the  cerebral  capillaries  are 
found  filled  with  parasites  in  those  who  have  died  with  coma. 

Other  pernicious  cerebral  forms  are  usually  associated  with 
parasitic  localizations. 

The  algid  variety,  while  possibly  sometimes  dependent  on 
toxemia,  is  usually  due  to  a  massing  of  parasites  in  the  gastro- 
intestinal mucosa.  This  is  explained  by  Davidson66  as  follows : 
"Experiments  show  that  the  alimentary  tract  is  in  closer  con- 
nection with  the  cardio-inhibitory  center  than  other  parts  of 
the  body,  and  that  irritation  of  this  tract,  if  sufficiently  power- 
ful, will  produce  cardiac  inhibition,  with  pallor  of  the  surface 
and  accumulation  of  the  blood  in  the  abdominal  vessels.  That 
the  intestinal  canal  is  the  center  of  mischief  in  this  form  of 
pernicious  attack  will  appear  all  the  more  probable  if  we  ob- 
serve the  character  of  the  disturbances  so  frequently  associated 
with  the  algid  condition — the  cardialgic  pain,  the  choleraic 
vomiting  and  purging,  and  the  dysenteric  discharges." 

ETIOLOGY  OF  HEMOGLOBINURIC  FEVER 
Etiologically  hemoglobinuria  fever  stands  in  the  same  rela- 
tion to  malaria  as  do  tabes  and  dementia  paralytica  to  syphilis, 
and  may,  very  properly,  be  regarded  as  a  "paramalarial"  infec- 
tion. 

Among  the  conditions  other  than  blackwater  fever  under 
which  hemoglobinuria  can  occur  may  be  mentioned  paroxysmal 
hemoglobinuria,  scarlet  fever,  typhus  and  typhoid  fevers,  acute 
articular  rheumatism,  leukemia,  pneumonia,  streptococcus  in- 
fection, chronic  suppurative  conditions,  after  extensive  burns 
or  freezing,  occasional  injuries,  rupture  of  ectopic  pregnancy, 
transfusion  of  blood,  injection  of  tuberculin,  poisoning  with 
phenocoll,  guaiacol,  pirodin,  salipyrin,  salicylic  acid,  antipyrin, 
sulphonal,  the  salts  of  chloric  acid,  phenol,  pyrogallic  acid,  sul- 
phuric, nitric,  and  hydrochloric  acids,  naphthol,  analine,  chrys- 
arobin,  toluylendiamin,  glycerine,  nitrobenzol,  potassium  chlo- 


154  THE   STUDY   OF   MALARIA 

rate,  phenacetin,  arseniuretted  hydrogen,  methylene  blue,  phos- 
phorus, oxalic  acid,  certain  illuminating  gases,  helvella  escu- 
lenta,  and  snake  venom.  Hemoglobinuria  is  a  common  symp- 
tom of  Texas  fever  in  cattle,  and  is  seen  occasionally  in  sheep, 
dogs,  goats,  horses,  and  mules,  following  infection  with  hema- 
tozoa  resembling  the  malarial  parasite. 

Race. — Hemoglobinuric  fever  is  chiefly  a  disease  of  the 
white  race.  The  negro  is  not  absolutely  immune,  though  not  a 
few  observers  of  wide  experience  have  not  seen  cases  in  this 
race.  This  relative  immunity  can  be  explained  only  by  natural 
selection.  It  varies  markedly  in  different  tribes,  and  members 
of  an  insusceptible  tribe  may  be  attacked  on  moving  to  a  black- 
water  fever  focus.  F.  Plehn5  refers  to  an  extensive  outbreak 
that  occurred  among  the  Cameroon  negroes,  especially  those 
who  came  from  the  interior  to  the  coast.  According  to  Drye- 
pondt,86  the  negroes  recruited  for  the  Congo  Free  State  in 
1890  to  1892  paid  a  large  tribute  to  this  malady.  DeGreny8 
saw  20  cases  in  negroes  imported  from  the  British  Antilles  for 
railroad  construction  work  on  the  lower  Congo.  In  the  medical 
report  from  German  East  Africa  for  the  official  year,  1903-4, 
there  were  listed  8  cases  in  negroes.  Corre,8  Donny,8  the 
younger  Moncorvo,8  Hanley,184  A.  Plehn,"  Rudolph  Plehn,185 
Wittrock,49  Brunn,49  Curry,180  Eyles,101  Doering,187  Reynolds,188 
Easmon,101  Wicke,90  Gaertner,90  Quartey-Papafio,101  O'Sulli- 
van-Beare,90  Vieth,90  Goltman  and  Krauss,189  McElroy,190 
Berenger-Feraud,191  Ziemann,86  Fisch,191  Ollwig,51  Greisert,51 
Lewis,192  Francez,193  Minor,194  McKay,195  Tyson,196  Gorgas,32 
and  Wendland49  have  seen  cases  in  negroes.  The  writer  has 
seen  two  cases  in  mulattoes  and  two  in  black  negroes.  Chinese 
imported  into  blackwater  fever  regions  are  almost  as  suscepti- 
ble as  whites.  Manson59  says  that  many  of  the  Chinese  labor- 
ers on  the  Congo  railway  died  of  hemoglobinuric  fever.  Im- 
ported Indians  are  affected,  but,  according  to  Daniels,197  are 
only  about  one-fourth  as  susceptible  as  Europeans.  As  may 
be  inferred  from  one  of  the  names,  "fievre  jaune  des  Creoles," 
Creoles  are  not  infrequently  attacked.  Masterman64  reports 
that  it  is  common  among  the  Jews  of  Palestine.  Rothschuh8 
saw  cases  in  mixed  breeds  and  pure  Indians  in  Nicaragua. 


ETIOLOGY 


155 


Sex. — Males  are  more  often  stricken  than  females,  the  lat- 
ter being  less  often  exposed  to  malarial  infection.  In  the  tem- 
perate zone  the  proportion  of  males  to  females  is  about  3 
to  1.  In  persons  under  fifteen  the  proportion  is  more  nearly- 
equal.  As  we  approach  the  equator  the  difference  becomes 
wider,  owing  to  the  relatively  small  number  of  susceptible 
females  and  children.  Daniels57  says  the  proportion  of  male  to 
female  cases  in  British  Central  Africa  is  15  to  1.  Car- 
damatis198  believed  that  pregnancy  conferred  immunity ;  how- 


Fig.  50. — Age  distribution  of  blackwater  fever  in  America. 

ever,  Krauss199  has  reported  a  case  in  a  pregnant  woman,  who 
made  a  tedious  recovery  after  abortion.  The  writer200  re- 
cently published  brief  notes  of  a  case  occurring  in  the  practice 
of  a  colleague.  The  woman  aborted  on  the  third  day  of  the 
disease  and  died  on  the  fourth.  Cases  have  often  been  observed 
to  follow  immediately  after  menstruation. 

Age. — In  America  more  than  half  the  cases  occur  before 
the  age  of  thirty,  though  very  young  children  are  relatively 
exempt.    In  the  tropics  it  is  commoner  in  the  third  and  fourth 


156  THE   STUDY  OF  MALARIA 

decades  of  life  because  most  of  the  susceptible  population  is 
within  these  ages.  Daniels57  saw  a  case  in  a  half-caste  about 
five  years  old;  Wendland,49  Van  der  Scheer,201  and  Karamit- 
sas15  observed  cases  in  children  of  four;  Lipari202  mentions  2 
cases  in  children  of  three;  Masterman64  1  in  a  girl  of  two,  and 
Oetker52  1  in  a  two-year-old  child;  Fisch203  saw  cases  in  chil- 
dren of  fourteen  months  and  two  and  one-half  years,  and 
McElroy204  1  at  twelve  months. 

Season. — In  the  tropics,  like  malaria,  it  is  perennial,  occur- 
ring without  marked  seasonal  prevalence,  though  probably  com- 
moner in  the  transition  period  from  the  moist  to  the  dry  season. 
In  the  temperate  zone  it  appears  at  the  height  of,  or  immedi- 
ately following,  the  malarial  season,  the  second  half  of  the 
year  showing  by  far  the  greater  number  of  cases,  especially 
August,  September,  and  October.  A  few  cases  are  seen  in  the 
first  six  months.  In  Greece  it  is  during  the  months  of  Novem- 
ber and  December  that  the  majority  of  cases  occur. 

Family  Predisposition. — Tomaselli205  believed  in  a  well- 
marked  family  tendency,  having  observed  cases  in  several  mem- 
bers of  the  same  family.  Daniels57  refers  to  three  families  in 
which  he  noticed  this  predisposition.  Three  such  families  are 
known  to  the  writer.  Cardamatis206  relates  the  case  of  a  family 
of  seven,  of  which  the  father,  mother,  and  one  daughter  were 
within  a  few  days  attacked  and  died  with  blackwater  fever. 
The  others,  removing  to  Athens,  were  all  subsequently  at- 
tacked, but  fortunately  recovered.  Nine  years  later  a  daughter 
had  the  fever  again  and  recovered.  Sutherland168  speaks  of  a 
family  of  which  all  the  children,  six  in  number,  died  with 
hemoglobinuric  fever. 

Idiosyncrasy. — An  idiosyncrasy  in  susceptible  individuals 
has  long  been  assumed  and  by  many  passively  accepted  as  the 
sole  explanation  of  the  mysteries  of  pathogenesis.  Foustanos207 
holds  that  idiosyncrasy  is  either  congenital  or  acquired,  as  the 
result  of  debility  or  bodily  changes  due  to  syphilis,  malaria, 
etc.  There  is  not  sufficient  evidence  to  show  that  heredity 
plays  an  important  part  in  whatever  is  meant  by  this  vague 
term. 

Previous   Attacks    of    Hemoglobinuria. — Who   has   had 


ETIOLOGY  157 

blackwater  fever  is  prone  to  have  recurrences.  In  the  tropics 
about  one-fourth  of  the  subjects  have  more  than  one  attack. 
Of  304  cases  mentioned  by  Cardamatis,  81  occurred  in  persons 
who  had  previously  had  it.  Several  tropic  physicians  record 
repeated  attacks  in  themselves.  Thus  F.  Plehn208  had  five  at- 
tacks, Crosse209  at  least  ten  severe  attacks,  and  Banks210  twelve 
or  thirteen  during  eighteen  years'  residence  in  Congo.  One  of 
Koch's172  patients  had  ten  attacks  in  one  year,  and  the  Plehns211 
state  that  they  know  persons  who  have  had  fifteen  or  more 
attacks.  There  is,  therefore,  no  active  immunity;  the  only 
immunity  except  natural  being  conferred  by  prolonged  resi- 
dence in  an  endemic  focus. 

Length  of  residence  in  the  home  of  the  disease  is  an  impor- 
tant factor,  A  curve  showing  the  number  of  first  attacks  to 
each  year  of  residence  would  rise  from  the  first  to  the  third 
years  and  then  fall  gradually.  This  is  almost  constant  for 
observation  in  the  tropics,  being  less  noticeable  in  temperate 
regions.  The  following  table  of  cases  seen  in  the  tropics  will 
illustrate : 

First      Second      Third      Fourth       Fifth     L  t 
year.       year.         year.         year.  year. 

Burot  and  Legrand,2"  100  cases. .. .     6  22  43  20  ..  9 

Daniels,"   114  cases 21  40  27  12  5  9 

Berenger-Feraud,96  185  cases 10  42  79  37  9  8 

Vedy,213  54  cases _6       8  29  _5  _H  _4 

43  112  178  74  16  30 

Fifty  cases  observed  by  McElroy214  in  the  Mississippi  Valley 
were  distributed  as  follows :  Two  in  the  first  year  of  residence, 
3  in  the  second,  6  between  the  second  and  the  fifth,  23  between 
the  fifth  and  the  tenth,  1 1  between  the  tenth  and  twentieth,  and 
5  after  twenty  years. 

Exceptionally  are  cases  seen  after  only  a  short  period  of 
tropic  residence,  as  Plehn's5  Case  XXXV,  after  two  months  in 
the  Cameroon,  and  one  of  Brem's215  cases,  after  two  months  on 
the  Isthmus  of  Panama.  Ziemann48  mentions  2  cases  begin- 
ning six  weeks  and  twenty-seven  days,  respectively,  after  arri- 
val in  a  malarial  locality,  and  Oeconomou15  observed  a  case 
occurring  after  ten  days  of  residence  in  a  malarial  region.  The 
case  showing  the  longest  period  of  residence  before  onset  in 


I58  THE  STUDY  OP  MALARIA 

which  this  is  specified  is  that  of  Howard,216  twenty-three  years 
in  Central  Africa,  though  in  5  of  McElroy's214  cases  the  length 
of  residence  was  longer  than  twenty  years. 

Altitude. — Hemoglobinuric  fever  is  often  considered  a 
disease  of  the  lowlands,  though  cases  are  commonly  observed 
at  heights  of  3,000  feet.  The  results  of  Daniels'57  observations 
on  the  influence  of  altitude  may  be  stated  as  follows : 

The  greater  number  of  recorded  cases  have  occurred  in  the 
highlands  at  or  about  3,000  feet  above  the  sea  level.  There 
are  two  reasons  for  this:  First,  the  number  of  residents  in 
these  highlands  is  much  greater  than  in  the  other  districts. 
This  correction  alone  reverses  the  figures;  secondly,  many  of 
these  cases  were  visiting  the  highlands  on  account  of  health  or 
for  other  reasons.  Others  were  passing  through  the  highlands 
when  invalided  home.  Some  had  recently  visited  the  lowlands. 
A  true  correction  that  would  attribute  each  case  to  the  district 
in  which  the  disease  was  acquired  is  impossible,  but  taking  an 
arbitrary  period  of  a  fortnight  as  representing  a  not  improbable 
latent  period  we  should  find  that  the  place  of  residence  a  fort- 
night or  more  previous  to  onset  would  give  a  very  different  dis- 
trict distribution  to  that  given  by  considering  the  place  of  onset. 
Corrected  for  proportional  numbers  of  susceptible  persons  in 
each  district  and  for  place  of  residence  two  weeks  previous  to 
onset,  the  distribution  per  10  of  population  is  as  follows:  1.04 
in  the  highlands,  7.28  at  the  lake  level  (Lake  Nyassa,  altitude 
about  1,500  feet),  and  3.8  in  the  lower  shire  regions.  Accord- 
ing to  Laveran,1  it  was  necessary,  on  account  of  the  frequency 
of  blackwater  fever,  to  abandon  certain  posts  in  Congo  estab- 
lished at  heights  of  500  to  700  meters. 

Change  of  residence  is  a  not  uncommon  cause  for  an  out- 
break, especially  if  the  difference  in  altitude  or  climate  is  de- 
cided. In  Africa  not  only  those  coming  from  the  mountains 
to  the  lowlands,  but  also  those  moving  from  the  insalubrious 
littoral  to  the  refreshing  high-lying  districts  are  predisposed. 
This  change  seems  to  be  independent  of  the  hardships  of  travel. 

After  Leaving  Endemic  Region. — Such  cases  have  been 
observed  in  England  by  Bassett- Smith,217  Hughes,218  Sylivan,8 
Crosse,4   Manson,219   Daniels,57  and  Parker;220  in  Ireland  by 


ETIOLOGY  159 

Mowbray;221  in  Germany  by  Schlayer,222  A.  Plehn,24  Kleine,223 
Koch224  and  F.  Plehn;211  in  France  by  Burot  and  Legrand,225 
Le  Dantec,226  Kelsch  and  Kiener,178  Rouvier,227  Vincent,8  Bois- 
son,86  Troussaint86  and  Laveran;1  in  Belgium  by  Dryepondt 
and  Vancanpenhout228  and  Bertrand;229  and  in  Baltimore  by 
Brem.215  Many  of  these  cases  were  not  mere  relapses;  indeed, 
in  the  majority  in  which  the  number  of  previous  attacks  was 
specifically  stated  they  were  first  attacks.  The  onset  may  occur 
from  a  few  days  to  five  months  or  more  after  leaving  the 
endemic  area.  Inclement  weather  and  fatigue  seem  to  be 
factors  in  some  of  these  cases.    The  mortality  is  low. 

Occupation  which  requires  residence  in  a  malarial  locality 
and  which  necessitates  overturning  of  the  soil,  as  gardening, 
farming,  ditching,  railroad  construction,  etc.,  is  largely  pre- 
disposing. Not  a  few  cases  occur  among  timber  workers. 
The  disease  prevailed  extensively  among  those  engaged  in  the 
construction  of  the  canal  of  Corinth.  Manson59  tells  us  that 
many  of  the  Chinese  laborers  on  the  Congo  railroad  died  of 
hemoglobinuric  fever,  and  DeGreny8  found  many  cases  in  both 
negroes  and  whites  in  the  railroad  work  on  the  lower  Congo. 
Crosse209  says  that  it  is  significant  that  his  first  three  gardeners 
died  of  blackwater  fever,  and  that  for  some  considerable  time 
cases  occurred  only  near  the  plantations,  and  as  the  plantations 
became  more  numerous  the  disease  spread  to  the  other  stations 
in  the  territories. 

Occasional  Causes. — Of  these,  exposure  to  cold  and  damp- 
ness is  probably  the  most  efficacious,  showing  somewhat  analo- 
gous to  paroxysmal  hemoglobinuria.  Overexertion  precedes 
some  cases.  The  influence  of  alcohol  has  probably  been  over- 
estimated. Trauma  has  a  slight  etiologic  importance.  Thus 
Mould230  mentions  a  case  developing  after  a  sprained  ankle; 
Plehn61  one  in  which  a  man  was  wounded  in  a  bush  fight  and 
bled  considerably.  Crosse209  and  Plehn5  saw  cases  immediately 
following  confinement.  Psychic  states,  as  anger,  grief,  and 
fear,  exposure  to  sun,  fatigue,  excessive  venery,  syphilis,  and 
the  mercury  cure  have  been  mentioned  as  occasional  causes. 
Cardamatis86  lays  stress  on  the  association  with  rheumatic 
diathesis,    12   of  his   30   cases   being   rheumatic.     Alexander 


l6o  THE   STUDY  OF  MALARIA 

Haig231  believes  there  is  an  intimate  relation,  most  probably- 
causative,  between  an  excess  of  uric  acid  in  the  blood  and 
hemoglobinuric  fever.  He  makes  the  unfounded  statement 
that  the  ordinary  acid  sulphate  of  quinine  is  about  one-fifth 
xanthin,  which  is  physiologically  and  pathologically  equivalent 
to  uric  acid,  and  herein,  he  believes,  lies  its  supposed  power  to 
produce  hemoglobinuria.  Johnson60  holds  that  a  meat  diet  pre- 
disposes to  blackwater  fever. 

Previous  Malaria. — It  may  be  said  with  almost  absolute 
certainty  that  previous  infection  with  malaria  is  essential.  In 
fact,  a  majority  of  careful  observers  make  the  unqualified 
assertion.  The  extreme  rarity  of  cases  in  which  preceding 
malarial  infection  is  denied  almost  forces  us  to  the  conclusion 
that  it  may  have  been  overlooked,  as  might  occur  in  latent  or 
masked  infection.  It  is,  however,  not  impossible  that  hemo- 
globinuria may  exceptionally  accompany  the  first  outbursts  of 
malaria,  as  in  cases  of  F.  Plehn,5  Goltman  and  Krauss,189  and 
Brem.215  In  all  of  the  cases  of  Tomaselli  and  Koch,  the  most 
ardent  advocates  of  the  quinine  theory,  there  was  a  history  of 
antecedent  malaria.  Tomaselli205  states  in  italicized  words  that 
the  two  conditions  which  favor  the  hemolytic  action  of  quinine 
are:  I,  Malarial  infection,  chronic  or  sometimes  recent;  2,  a 
special  idiosyncrasy  often  hereditary. 

Cardamatis206  cites  several  writers  who  have  seen  cases  with- 
out preceding  malaria,  and  Van  der  Scheer201  is  said  to  have 
seen  such  a  case. 

Pathogenesis. — There  are  three  chief  theories  as  to  the 
nature  of  hemoglobinuric  fever:  1,  that  it  is  malaria;  2,  that 
it  is  quinine  poisoning;  3,  that  it  is  a  disease  sui  generis. 

I.  Against  the  malarial  nature  of  hemoglobinuric  fever  may 
be  urged  the  following  objections : 

1 .  The  parasites  are  often  absent ;  when  present  they  are  not 
numerically  proportionate  to  the  severity  of  the  attack,  and 
usually  disappear  as  the  disease  progresses;  sporulation  does 
not  correspond  in  time  with  the  symptoms;  hemoglobinuria 
may  be  associated  with  different  forms  of  the  malaria  parasite. 

2.  In  malaria  very  numerous  parasites  may  be  present  with- 
out producing  hemoglobinuria. 


ETIOLOGY  l6l 

3.  The  geographic  range  does  not  coincide  with  that  of 
malaria. 

4.  Its  seasonal  prevalence  does  not  correspond  with  that  of 
malaria. 

5.  Black  water  fever  is  not  amenable  to  quinine. 

The  frequency  with  which  the  parasites  are  found  is  shown 
by  the  following  list  of  examinations  by  various  observers. 
The  first  column  of  figures  shows  the  number  of  examinations 
made,  the  second  the  number  in  which  the  parasites  were 
present : 

Kanellis232    20  10 

Bignami  and  Bastianelli233 2  1 

Vincent8   e 

Dryepondt  and  Vancanpenhout228 ...                            1  n 

Powell234   '    IT  5 

Koch172    l6  % 

~tt™WS\.--3 13 

Cardamatis        oe  a 

Burns235    '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.     3  3 

Boisson88    o  o 

Daniels" "                          '   £  6A 

Wellman50    ...'.'..'.'.'.'.'.':'.'.'.'.'.'.'.'.     1  f 

Crosse230   '     T 

Brem215    ...'.'.'.'.'.   14  2 

Krauss199  „  7 

McElroy214   2?  i 

Thin237.... .'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'     1  0 

Kleine223    Te  g 

Hoffman49    3  2 

Curry186 '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'..'.     2  o 

Troussaint88    j  e 

Pezopoules  and  Cardamatis88 7  ■? 

Ketchen238    ..'.'.'.'.'.     1  1 

Mastermann64 1  1 

Schlayer222    T 

onwig49 ...:.::::::::::::::::  T5  6 

Stephens  and  Christophers" 16  1 

Howard218    T  ^ 

Ruge- ..:,:::..::::::::::::  i  ° 

Goltman  and  Krauss189 1-? 

Woldert248    .....'.'.'.'.'.'.'.'.'.     1 

Hartsock241    T  0 

F.  Plehn5 '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.   33  22 

Broden242    20  g 

Marchoux243  '.'.'.'.'.     g  1 

Oeconomou243    ->  0 

Cardamatis244    2=5  a 

Le   Dantec220 '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.     3  o 

Bernardo245    20  17 

Gauducheau245  Tr  0 

Da  Costa245 20  ic 

Grattan240    ri  * 

Kuiz2" :::::::::::::::::::  16  1 

Kudicke"   „  n 

Wellman08    \ /.  , 

11                                                          J4  3 


4 


1 62  THE   STUDY  OF   MALARIA 

As  stated  in  the  first  objection,  the  parasites  when  present 
tend  to  disappear  as  the  disease  progresses.  The  following 
figures  show  the  difference  in  results  of  examination  at  differ- 
ent periods.  The  great  frequency  with  which  they  are  found 
the  day  before  the  attack  should  be  noted : 

Stephens  and  Christophers  :11S 

Day  before  attack  parasites  present  in  95  per  cent,  of  cases. 

Day  of   attack   parasites    present    in    70   per    cent,    of  cases. 

Day  after  attack  parasites  present  in  20  per  cent,  of  cases. 

Mannaberg  :111 

Day  before  attack  parasites  present  in  95.6  per  cent,  of  cases. 
Day  of  attack  parasites  present  in  63  per  cent,  of  cases. 
Day  after  attack  parasites  present  in  17.1  per  cent,  of  cases. 

The  reasons  for  the  rapid  disappearance  of  the  organisms 
are,  first,  that  often  quinine  has  been  taken  before  the  examina- 
tion; secondly,  that  in  the  terrific  hemolysis  the  weaker  cells, 
including  those  containing  parasites,  are  usually  the  first  to 
succumb. 

The  hemoglobinuria  occurring  in  Texas  fever  of  cattle  is 
cited  with  some  show  of  reason  as  an  argument  for  the  purely 
malarial  origin  of  blackwater  fever.  There  are  essential  dif- 
ferences, however,  in  the  occurrences  of  blackwater  in  malaria 
and  Texas  fever.  First,  malaria  is  followed  by  blackwater  in 
a  very  small  percentage  of  cases,  malaria  being  common,  hemo- 
globinuric  fever  much  rarer;  in  Texas  fever  blackwater  is  a 
common  symptom,  occurring  in  nearly  all  severe  cases.  Second, 
in  blackwater  fever  in  man  the  number  of  parasites  shows  no 
proportion  whatever  to  the  severity  of  the  disease.  In  Texas 
fever,  on  the  other  hand,  as  is  shown  by  Smith  and  Kil- 
bourne,248  the  number  of  parasites  is  in  direct  relation  to  the 
severity  of  the  process  and  increases  as  a  fatal  termination 
approaches.  In  human  malaria  the  parasites  may  exist  in  very 
large  numbers  without  the  development  of  hemoglobinuria; 
this  is  not  the  case  in  Texas  fever.  Bonome  found  in  the 
icterohemoglobinuria  of  sheep  the  same  relation  between  the 
number  and  behavior  of  the  hematozoa  and  the  intensity  and 
progress  of  the  attack  as  obtains  with  Texas  fever. 

The  form  of  parasite  found  in  blackwater  fever  is,  in  the 
great  majority  of  instances,  the  estivo-autumnal.     Only  excep- 


ETIOLOGY  163 

tionally  is  hemoglobinuria  combined  with  infections  with  the 
benign  organisms.  The  tertian  parasite  has  been  observed  in 
cases  of  Ziemann,48  Panse,79  Orme,249  Pecori,69  Carducci,69  Van 
der  Horst,250  Hughes,218  Koch234  (5  cases),  A.  Plehn"  (3 
cases),  Ollwig,49  McElroy,214  Goltman  and  Krauss,189  Brem,215 
Herrick251  and  Curl251  (3  cases).  The  quartan  parasite  has 
occurred  in  cases  of  Vincenzi,96  Grocco,96  Kleine,223  Kudicke,51 
and  Otto.53  Thiroux86  and  Laveran11  are  said  to  have  found 
the  large  form  of  parasite,  but  whether  tertian  or  quartan  is 
not  stated.  The  fact  that  parasites  other  than  estivo-autumnal 
have  been  found  is  no  argument  against  the  malarial  nature 
of  blackwater  fever,  since  cases  of  pernicious  malaria  in  which 
only  the  large  tertian  parasites  were  found  have  been  reported 
by  French,166  Ewing181  (2  cases),  Ziemann,48  and  others. 

Some  writers  believe  that  in  addition  to  the  mechanical  de- 
struction of  the  red  cells  by  the  parasites  the  latter  give  off 
toxins  which  have  hemolytic  powers.  The  facts,  however, 
that  intense  hemolysis  may  occur  with  very  few  parasites  in 
the  blood,  and  that  the  parasites  when  present  do  not  bear  a 
direct  relation  to  the  severity  of  the  disease,  but  rapidly  dimin- 
ish as  the  disease  progresses,  speak  strongly  against  the  role 
of  a  parasitic  toxin  in  blackwater  fever. 

The  number  of  cases  in  which  the  parasite  is  found  if  the 
examination  is  made  early  constitutes  conclusive  evidence  of 
an  intimate  relationship  to  malaria.  This,  however,  is  not  all. 
The  testimony  furnished  by  the  parasites  is  corroborated  by 
the  two  subsidiary  evidences  of  malaria :  first,  pigmented  leuko- 
cytes; secondly,  mononuclear  leukocytosis.  Given,  therefore, 
the  presence  of  the  parasites  in  the  first  hours  of  attack,  and 
the  almost  constant  finding  of  pigmented  leukocytes  and 
mononuclear  leukocytosis,  it  is  impossible  to  deny  that  malaria 
plays  an  important  role  in  its  production. 

The  peculiarity  of  the  geographic  distribution  of  hemo- 
globinuric  fever  is  no  argument  against  its  malarial  nature. 
While  it  does  not  occur  in  all,  even  highly,  malarial  countries, 
it  is  not  met  except  in  markedly  miasmatic  regions.  Neither 
does  the  distribution  of  quartan  fever  or  some  forms  of  perni- 
cious fever  coincide  with  that  of  malaria  in  general.     Nor  is 


164  THE   STUDY   OF   MALARIA 

the  slight  difference  of  seasonal  prevalence  of  any  weight. 
The  different  forms  of  malaria  have  different  seasons  of  preva- 
lence, as  "spring  tertian,"  and  estivo-autumnal. 
Favorable,  therefore,  to  malarial  character  are : 

1.  Geographic  distribution. 

2.  Length  of  residence  in  endemic  region. 

3.  Previous  attacks  of  malaria. 

4.  Malarial  prophylaxis  is  prophylactic  of  blackwater  fever. 

5.  Blood  findings :  parasites,  pigmented  leukocytes,  mono- 
nuclear leukocytosis. 

The  fact  that  hemoglobinuric  fever  does  not  respond  to 
quinine  is  one  of  the  strongest  evidences  that  it  is  not  an  attack 
of  malaria  {per  se). 

The  writer's  opinion  of  the  relation  of  malaria  to  blackwater 
fever  is  that  the  former  is  essentially  and  solely  the  predispos- 
ing cause,  and  that  in  some  cases  it  may  also  act  as  the  exciting 
cause. 

II.  Tomaselli  first  published  his  observations  as  to  the  etio- 
logic  relation  between  quinine  and  blackwater  fever  in  1874. 
More  recently  Koch  has  directed  attention  toward  it.  The 
widespread  controversy  that  followed  the  publication  of  Koch's 
views  was  bitter  in  the  extreme ;  the  matter  was  even  aired  in 
the  London  lay  press.  The  misunderstanding  was  probably 
due  to  two  causes ;  first,  ignorance  of  Koch's  utterance  at  first 
hand ;  secondly,  the  somewhat  non-committal  manner  in  which 
he  expresses  his  idea  of  the  relation  to  malaria.  While  he  is 
very  emphatic  that  blackwater  fever  is  not  an  attack  of 
malaria,  he  is  not  clear  as  to  the  predisposing  role  of  the  latter. 
He  does  not  even  assert  that  quinine  is  the  exciting  cause  in  all 
cases,  but  admits  that,  although  he  saw  no  cases  of  blackwater 
fever  in  which  quinine  could  be  excluded,  he  could  not  go  so 
far  as  to  maintain  that  every  case  of  blackwater  fever  is 
quinine  poisoning.172  There  is  no  doubt  but  that  this  acrid 
dispute  was  productive  of  dire  results,  inasmuch  as  it  brought 
the  specific  into  discredit  not  only  with  the  laity,  but  with 
many  of  the  profession.  Even  yet  it  is  necessary  in  some  places 
on  account  of  a  fear  of  hemoglobinuria  to  disguise  quinine 
before  it  can  be  given. 


ETIOLOGY  165 

Tomaselli205  was  able  to  collect  from  the  literature  only  102 
cases  of  quinine  hemoglobinuria. 

The  objections  to  the  quinine  theory  are : 

1.  Hemoglobinuria  is  restricted  in  geographic  range,  and 
is  absent  from  some  highly  malarial  localities  where  much 
quinine  is  used. 

2.  Hemoglobinuria  does  not  follow  the  administration  of 
quinine  for  maladies  other  than  malaria. 

3.  In  a  considerable  number  of  cases  the  antecedent  use  of 
quinine  can  be  eliminated  with  certainty. 

4.  The  same  individual  may  have  an  attack  following  the 
administration  of  quinine,  and  later  take  it  without  harmful 
results. 

5.  The  severity  of  the  attack  bears  no  relation  to  the  size 
of  the  dose. 

6.  One  dose  of  quinine  could  not  cause  intermittent  hemo- 
globinuria. 

7.  The  great  majority  of  cases  recover  even  under  the  con- 
tinued use  of  large  doses  of  quinine. 

Objections  1,  2,  and  6  go  to  demonstrate  that  other,  and 
probably  more  important,  factors  than  quinine  are  at  work 
even  in  cases  often  attributed  to  it.  Objections  4  and  7  are 
not  potent  if  we  assume  that  only  a  portion  of  the  erythrocytes 
are  susceptible  to  the  effects  of  quinine,  and  that  all  these  are 
destroyed  by  the  first  dose.  Objection  5  proves  that  in  cases 
where  an  outbreak  occurs  after  quinine  it  cannot  be  regarded  as 
mere  quinine  poisoning.  The  third  is  the  strongest  argument 
against  the  theory  that  all  blackwater  fevers  are  cases  of 
quinine  poisoning.  That  quinine  is  not  always  the  exciting 
cause  is  fully  attested  by  the  numerous  cases  in  which  no 
quinine  had  been  given,  as  observed  by  Boye,2r'2  Vedy,213  Doer- 
ing,253  Broden,242  Ellenbeck-Hilden,254  Legrain,255  Grail,250 
Rossoni,257  F.  Plehn,208  A.  Plehn24  (22  cases),  Marchiafava,234 
Celli,234  Bastianelli,234  Beyfuss,234  Van  der  Scheer,234  Seal,258 
Powell,234  Von  Diesing,234  Carre,234  Schellong,234  Laveran,1 
Quennec,234  Navarre,234  Reynolds,234  Etienne,234  Sims,234 
Donny,234  Dryepondt,234  Mense,234  Rothschuh,8  Fluit,8  R. 
Plehn,185  Dempwolff,185  Brin,185  Crosse,230  Thin,237  Stalkarrt,259 


166  THE   STUDY  OF   MALARIA 

Hopkins,260  Cargill,261  Mould,230  Hoffmann,49  Daniels,57  Ran- 
kin,262 Cardamatis206  (32  cases),  Yofe,86  Moffatt,263  Schlayer,222 
Curry,186  McElroy,264  DuBose,265  .  Hearsey,266  Ziemann,86 
Brem,215  Bignami,234  Doering185  and  Shropshire267  (15  per  cent, 
of  his  cases).  The  writer  has  seen  4  cases  where  quinine  could 
be  excluded  from  the  etiology. 

Hemoglobinuric  fever  occurring  only  in  malarial  subjects 
and  quinine  being  specific  for  malaria,  it  is  but  a  most  natural 
sequence  of  events  that  a  large  number  of  the  cases  of  hemo- 
globinuric fever  have  developed  after  the  administration  of 
quinine.  The  bare  fact  that  black  water  fever  often  follows 
quinine  is  weak  evidence  for  quinine  etiology  in  the  face  of 
the  numerous  cases  in  which  previous  quinine  could  be  abso- 
lutely excluded. 

When,  however,  attacks  can  be  produced  repeatedly  at  will 
by  a  dose  of  quinine  the  question  assumes  a  very  different 
aspect.  Such  cases  are  those  of  Murri,268  Hoffman,49  Koch,172 
Manson,213  Ketchen,238  Hopkins,200  Bertrand,229  A.  Plehn,24 
Ollwig,49  Marsden,269  Daniels,57  Kleine,223  Tomaselli,205  Vin- 
cenzi,96  and  Grocco.96 

As  stated  above,  there  is  no  relation  between  the  amount  of 
quinine  and  the  intensity  of  the  attack.  Ketchen23S  precipi- 
tated an  attack,  experimentally,  with  1  ^2  grains.  This  patient 
stated  that  one-eighteenth  of  a  gram  had  previously  produced 
blackwater.  Karamitsas,80  Chomatianos,86  Pampoukis,86  Kanel- 
lis,86  Koch,172  Kleine,223  Shropshire,267  Moscato,86  A.  Plehn,24 
Boxer,270  and  others  report  outbreaks  elicited  by  less  than  one- 
half  gram.  Panse252  believes  that  the  usual  dose  preceding  an 
outbreak  to  be  from  one-tenth  to  1  gram.  Tomaselli205  has 
observed  attacks  to  follow  the  administration  of  doses  as  small 
as  from  one-twentieth  to  one-tenth  gram,  and  Koch271  reports 
a  case  after  one-tenth  gram  had  been  administered.  Kudicke51 
and  Marchiafava  and  Bignami22  state  the  minimum  quantity 
as  one-twentieth  gram,  Laveran1  and  Ziemann48  as  1  centi- 
gram, and  Ruge158  as  1  milligram. 

Tomaselli205  examined  various  preparations  of  quinine  to 
ascertain  whether  the  toxic  effect  was  dependent  upon  adultera- 
tion, and  concluded  that  such  was  not  the  case,  but  that  the 


ETIOLOGY  167 

toxic  properties  were  inherent  to  quinine  itself  and  to  all  the 
preparations  containing  quinine. 

The  time  intervening  between  the  administration  of  quinine 
and  the  onset  of  hemoglobinuria  is  almost  uniformly  fixed  by 
various  observers  at  from  one  to  six  hours.  With  six  hours 
as  the  maximum  interval,  the  cases  really  due  to  quinine  would 
dwindle  considerably. 

It  is  believed  by  some  writers  that  quinine  hypodermically 
does  not  produce  blackwater,  even  in  persons  susceptible  when 
administered  orally.  This,  however,  is  not  the  case.  Toma- 
selli205  has  shown  that  subcutaneous  injections  of  quinine  are 
followed  more  promptly  by  hemoglobinuria  than  is  the  oral 
administration.  Kohlbrugge7  thinks  that  only  the  inorganic 
salts  of  quinine  are  toxic,  and  states  that  the  tannate,  even  in 
the  largest  doses  given  to  susceptible  persons,  fails  to  cause 
hemoglobinuria.  McKay449  has  recently  attempted  to  show 
that  hemolysis  following  the  administration  of  the  sulphate 
of  quinine  is  due  to  the  sulphate  and  not  to  the  quinine.  This 
view,  however,  is  not  supported  by  clinic  experience.  Further- 
more, the  results  of  experiments  upon  which  McKay  based 
his  conclusion  could  not  be  verified  by  Christophers  and  Bent- 
ley.  It  is  probable  that  neither  the  mode  of  administration 
nor  the  preparation  used,  if  absorbed,  gives  any  difference  in 
results. 

The  role  of  quinine  in  hemoglobinuric  fever  is  probably 
highly  complex.  It  will  be  shown  that  it  is  of  value  as  a 
prophylactic  when  systematically  employed;  if  not  thus  used, 
and  malarial  infection  be  permitted  to  occur,  it  may,  in  some 
persons  thus  predisposed,  act  as  the  exciting  cause.  In  the 
attack  itself  it  is  possibly  of  value  in  destroying  the  parasites 
when  these  are  present,  or  it  may  act  harmfully  in  aiding  hemo- 
lysis. 

Even  after  a  careful  study  it  is  not  easy  to  define  precisely 
the  respective  potency  of  malaria  and  quinine  as  etiologic  fac- 
tors. To  quote  Shropshire  :2G7  "To  establish  the  cause  of  any 
disease  we  must  apply  the  agent  to  the  subject,  and  have,  as 
uniform  result,  the  disease.  But  if  there  are  two  agents  sus- 
pected as  causative  which  applied  together  produce  the  disease, 


1 68  THE   STUDY  OF  MALARIA 

but  applied  separately  to  the  same  individual,  the  one  produce 
it,  the  other  never,  we  can  attribute  only  to  the  one  a  causative 
place,  and  to  the  other  an  accidental  presence.  Such  is  the 
case  before  us.  Malaria  taken  as  the  cause  and  applied  with- 
out quinine  to  an  individual  of  such  tendency,  hemoglobinuria 
results  in  15  per  cent,  of  the  cases  before  us.  Quinine  has 
probably  been  applied  to  all  the  cases  before  us  without  the 
presence  of  malaria  and  no  hemoglobinuria  resulting.  Which 
produces  it  ?" 

Favoring  malaria  as  against  quinine  we  have : 

1.  Antecedent  malaria  essential. 

2.  Relative  immunity  of  the  negro.  Racial  immunity  to 
disease  well  known;  racial  susceptibility  to  drugs  rare  or  un- 
known. 

3.  Occurs  often  without  the  administration  of  quinine. 

We  may  safely  conclude  that  the  predisposing  cause  is  al- 
ways malaria;  the  exciting  causes  are  fresh  malarial  invasion, 
quinine  or  other  medicaments,  exposure,  exertion,  mental 
states,  etc. 

III.  The  most  enthusiastic  champion  of  the  view  that  black- 
water  fever  is  neither  malaria  nor  quinine  poisoning,  but  a 
disease  sui  generis,  is  Sambon.121  Manson272  formerly  advo- 
cated this  theory.  .  The  two  reasons  for  his  belief  are  a  simi- 
larity to  paroxysmal  hemoglobinuria  and  an  analogy  with 
Texas  fever.  Stalkarrt,259  Rho,273  Vincent,8  and  others  be- 
lieve that  it  is  a  distinct  disease.  While  the  similarity  to 
paroxysmal  hemoglobinuria  cannot  be  denied,  the  relation  to 
Texas  fever,  as  we  have  seen,  is  far  from  close,  and  the  evi- 
dence that  it  is  a  disease  sui  generis  is  inadequate.  Yersin274 
found  bacilli  in  the  casts  and  epithelium  in  the  urine  of  2 
patients,  and  believed  that  he  had  discovered  the  cause  of  the 
disease.  Breaudat,275  however,  showed  that  these  were  the 
bacillus  Coli  communis. 

Collet276  has  recently,  without  grounds,  however,  suggested 
that  there  may  be  a  causal  relation  between  the  bacillus  Mega- 
therium and  blackwater  fever. 

The  theory  that  green  beans  and  their  blossoms  were 
the    cause    of    many    cases    of    hemoglobinuric    fever    seems 


ETIOLOGY  169 

to  have  perished  in  Greece,   Sicily,   and   Sardinia,   where   it 
originated. 

It  is  generally  conceded  that  hemoglobinuric  fever  consists 
of  a  destruction  of  red  blood-cells  so  widespread  that,  the 
liver  being  powerless  to  transform  the  liberated  hemoglobin 
into  bile  pigment,  the  greater  part  is  excreted  by  the  kidneys. 
This  conversion  into  biliary  coloring  matter  is  the  physiologic 
fate  of  free  hemoglobin,  and  indeed  its  pathologic  destiny  up 
to  a  certain  limit — which,  according  to  Ponfick's  postulate,  is 
the  destruction  of  one-sixth  of  the  entire  number  of  red  cells — 
beyond  which  hemoglobinuria  ensues.  This  much  seems  to 
be  rather  unanimously  accorded.  The  nature  of  the  hemolysin 
is  the  missing  link  in  the  pathogenetic  chain. 

The  modern  study  of  immunity  and  cytolysis  has  thrown 
a  flood  of  light  on  hemolysis.  It  is  unnecessary  to  review  in 
detail  the  development  of  our  knowledge  of  hemolysis,  but 
the  following  facts  will  be  recalled.  It  has  been  known  for 
some  time  that  the  serum  of  certain  animals  has  the  power 
of  dissolving  the  blood  corpuscles  of  certain  other  animals. 
Bordet  showed  that  this  effect  may  be  produced  artificially. 
The  serum  of  guinea-pigs  naturally  has  no  hemolytic  effect 
on  the  red  cells  of  the  rabbit,  but  if  the  rabbit's  blood  is  in- 
jected into  the  guinea-pig  and  the  process  repeated  the  serum 
of  the  guinea-pig  becomes  hemolytic  toward  the  rabbit.  It 
has  been  shown  that  the  hemolysins  are  formed  by  the  inter- 
action of  two  substances,  one,  the  amboceptor  or  immune  body, 
resisting  moderate  degrees  of  heat ;  the  other,  called  the  com- 
plement, inactivated  by  a  temperature  of  about  55°  C.  Neither 
amboceptor  nor  complement  alone  is  sufficient  to  dissolve 
erythrocytes,  but  for  this  it  is  necessary  that  both  act,  the 
amboceptor  sensitizing  the  cells  for  the  complement.  The 
amboceptor  may  act  alone,  but  the  cells  will  only  be  rendered 
susceptible,  not  dissolved.  The  complement  has  no  effect 
whatever  on  the  red  cells  except  through  the  immune  body. 
The  complement  exists  in  normal  serum.  The  formation  of 
an  anti-hemolysin  is  thus  stated  by  Wasserman  :277  "Specific 
hemolysin,  one,  for  example,  specific  for  rabbit's  blood,  de- 
rived by  treating  a  guinea-pig  with  rabbit's  red  cells,  is  highly 


170  THE   STUDY   OF   MALARIA 

toxic  to  rabbits.  Injected  into  the  animals  intravenously  in 
doses  of  5  cc.  it  quickly  kills  the  animals,  causing  intra  vitam 
a  solution  of  red  cells.  Such  a  hemolytic  serum  then  acts  the 
same  as  a  bacterial  poison.  For  example,  to  keep  to  our  illus- 
tration, rabbits  are  injected  first  with  very  small  doses  of  this 
specific  hemolytic  serum.  The  dose  is  gradually  increased 
until  it  is  found  that  the  animal  tolerates  amounts  that  would 
be  absolutely  fatal  to  animals  not  so  treated.  If  some  of  the 
serum  of  this  animal  is  now  abstracted  and  added  to  the 
specific  hemolytic  serum  it  is  found  that  the  power  of  the 
latter  will  be  inhibited.  This  shows  that  an  antihemolysin 
has  been  formed." 

These  statements  refer  to  the  employment  of  heterologous 
serum;  that  is,  the  serum  of  different  species  of  animals. 
Isolysis,  due  to  the  employment  of  blood  of  the  same  species, 
is  exemplified  in  cases  following  the  transfusion  of  blood 
from  man  to  man.  Examples  of  autolysis,  due  to  the  blood 
of  the  individual,  are  cases  that  have  occurred  after  resorption 
of  extravasated  blood,  as  the  rupture  of  ectopic  pregnancy. 

Based  on  these  facts,  which  have  been  amply  demonstrated, 
Bignami22  states  his  theory  as  follows : 

1.  An  alteration  in  the  plasma  which  is  effected,  little  by 
little,  as  a  consequence  of  a  specific  change  in  the  red  blood 
corpuscles  through  which  a  certain  number  of  them  come  to 
behave,  in  respect  to  the  organism,  like  the  corpuscles  in  the 
blood  of  another  species  of  animal.  2.  The  formation  in 
consequence  of  this  change  of  a  substance  in  the  plasma  which 
is  capable,  under  certain  conditions,  of  becoming  hemolytic. 

The  writer278  some  time  ago  modified  and  elaborated  Big- 
nami's  hypothesis,  and  expressed  it  for  the  first  time  in  the 
terms  of  Ehrlich's  side-chain  theory. 

For  the  better  understanding  of  the  writer's  hypothesis  the 
pathogenesis  may  be  divided  into  the  following  stages:  1, 
erythrorrhexis ;  2,  hepatic  stimulation  and  production  of  ambo- 
ceptors; 3,  action  of  complement;  4,  hemolysis  and  hemo- 
globinuria, or  the  formation  of  an  antihemolysin. 

1.  This  primary  blood  destruction  is  due  directly  to  the 
malarial  parasite,  chiefly  through  the  act  of  sporulation,  possi- 


ETIOLOGY  171 

bly  also  by  the  production  of  a  toxin.  The  hemoglobin  thus 
liberated  is  carried  to  the  liver,  where  it  is  elaborated  into  bile 
pigment.  We  have  seen  that  this  erythrorrhexis  is  insufficient 
to  account  for  hemoglobinuria. 

2.  On  reaching  the  liver  the  hemoglobin  is  acted  upon  by 
certain  of  the  molecules  or  atom  groups  of  the  liver-cells, 
which  have  an  affinity  for  it.  When  all  of  the  atom  groups 
have  been  combined  with  by  the  hemoglobin,  which  happens 
when  this  function  of  the  liver  has  been  frequently  or  recently 
exerted,  or  when  the  amount  of  liberated  hemoglobin  is  very 
large,  the  liver  is  stimulated  to  the  production  of  more  such 
atom  groups.  This  stimulation  is  responded  to  by  an  over- 
production of  atom  groups,  some  of  which  gain  access  to  the 
general  circulation.  Translated  into  the  terms  of  Ehrlich's 
theory,  it  may  be  said  that  certain  receptors  of  the  liver  cells 
have  the  property  of  transforming  free  hemoglobin  into  bile 
pigment;  when  these  receptors  are  exhausted  the  deficiency  is 
met  by  overproduction.  When  the  cells  become  overfilled  some 
of  these  side-chains  are  cast  off  into  the  general  circulation. 
Here  the  receptor  becomes  an  amboceptor.  The  pathology  of 
the  liver  in  this  condition  fully  supports  the  view  of  over- 
stimulation. Karyokinesis  and  other  changes  in  the  liver 
cells  suggest  that  it  responds  to  this  stimulation.  In  the  pres- 
ent state  of  our  knowledge  we  cannot  determine  the  chemic 
nature  of  the  immune  body. 

3.  Having  gained  access  to  the  general  circulation,  the 
amboceptor  meets  the  complement  which  is  present  in  normal 
serum,  and  the  complete  hemolysin  is  formed. 

4.  The  reaction  of  amboceptor  with  complement,  if  not 
antagonized  by  an  antihemolysin,  causes  a  hemolysis,  which  if 
sufficiently  extensive  results  in  hemoglobinuria.  It  is  highly 
probable  that  when  the  production  of  the  hemolysin  does  not 
proceed  with  too  great  rapidity  there  is  formed,  parri  passu, 
an  antihemolysin,  which  may  exactly  balance  the  hemolysin 
without  destroying  it.  This  is  probably  the  symbiosis  referred 
to  by  Krauss.199  So  long  as  the  equilibrium  between  hemo- 
lysin and  antihemolysin  is  maintained  no  hemolysis  occurs, 
but  let  this  equilibrium  be  greatly  disturbed  by  fresh  malarial 


172  THE   STUDY   OF  MALARIA 

invasion,  quinine,  exposure,  fatigue  or  other,  and  probably- 
unknown,  factors,  hemolysis  occurs  and  hemoglobinuria  en- 
sues. Under  this  exact  equilibrium  the  subject  may  be  said 
to  possess  idiosyncrasy,  and  is  in  a  condition  very  similar  to 
that  of  paroxysmal  hemoglobinuria.  Casagrandi82  has  re- 
cently found  in  malarial  blood  a  hemolysin  the  presence  of 
which  is  masked  by  an  antihemolysin. 

It  is  possible  that  a  slight  and  temporary  loss  of  equilibrium 
may  result  in  a  limited  hemolysis  producing  hemoglobinemia, 
but  not  hemoglobinuria.  In  this  way  may  be  explained  some 
cases  of  anemia,  cachexia,  and  post-malarial  secondary  fever, 
in  which  the  parasites,  if  present,  are  not  in  proportion  to  the 
results. 

It  is  believed  that  this  hypothesis  explains  the  occurrence 
of  hemoglobinuric  fever  during  and  after  malarial  infection, 
with  or  without  the  administration  of  quinine ;  it  explains  why 
the  malarial  attack  may  precede  by  months  the  appearance  of 
blackwater;  why  exposure,  exertion,  etc.,  may  elicit  an  attack; 
why  the  hemolysis  does  not  always  coincide  in  time  with  the 
sporulation  of  the  parasites  in  the  cases  in  which  the  latter 
are  present ;  it  accounts  in  a  measure  for  the  complex  relation 
with  quinine  and  explains  obscure  anemia,  quinine  fever,  post- 
malarial  secondary  fever,  and  post-hemoglobinuric  fever. 
Lastly,  it  coincides  with  the  prevalent  ideas  of  tropic  physicians 
of  an  intimate  relation  between  hemoglobinuric  fever  and 
"biliousness." 

Christophers  and  Bentley,279  constituting  a  committee  ap- 
pointed by  the  Government  of  India  to  conduct  an  inquiry 
regarding  the  nature  of  blackwater  fever,  have  recently  pub- 
lished an  extensive  monograph  containing  a  record  of  their 
experiments  and  the  conclusions  which  they  reached  as  a  re- 
sult of  these  experiments.  They  exclude  parasitic,  osmotic, 
and  chemic  actions  as  causes  of  hemolysis,  and  show  that  the 
hemolysin  is  probably  derived  from  auto-immunization  against 
the  organism's  own  red  cells,  an  autolysin,  confirming  thus 
far  Bignami's  and  the  writer's  theory.  These  experiments, 
which  are  the  most  complete  and  convincing  that  have  been 
conducted  in  connection  with  hemoglobinuric  fever,  are  too 


ETIOLOGY  173 

extensive  to  be  abstracted,   and  should  be  consulted  in  the 
original  by  those  interested. 

According  to  the  conditions  of  its  occurrence  hemoglobin- 
uric  fever  is  classified  by  the  Italian  school  as  follows : 

1.  Malarial  hemoglobinuria : 

(a)  Cases  in  which  the  blood  contains  parasites. 

(b)  Cases  in  which  no  parasites  are  present. 

2.  Quinine  hemoglobinuria  in  malarial  subjects,  occurring: 

(a)  During  the  malarial  attack. 

(b)  After  the  attack  (post-hemoglobinuric). 


CHAPTER  IV 

PATHOLOGIC  ANATOMY 

ACUTE  MALARIA 

The  pathognomonic  anatomic  feature  of  malaria  is  intra- 
vascular melanin,  which  is  a  product  of  hemoglobin  converted 
through  the  biologic  agency  of  the  malarial  parasites.  Mela- 
nin occurs  in  the  tissues  also,  but  here  there  is  some  doubt 
as  to  its  origin.  It  is  brownish  black  in  color,  occurs  in  fine 
grains,  coarse  particles,  or  in  lumps;  does  not  yield  the  reac- 
tion for  iron,  and  is  insoluble  in  acids,  but  is  readily  dissolved 
by  ammonium  sulphide.  This  should  not  be  confused  with 
hemosiderin,  which  is  a  chemic  derivative  of  the  hemoglobin 
of  broken-down  red  blood-cells ;  is  yellowish  in  color ;  responds 
to  the  reaction  for  iron;  is  insoluble  in  acids,  alkalies,  alcohol, 
and  water,  and  exists  especially  extravascularly.  It  is  regarded 
as  a  result  of  prolonged  hemoglobinemia  following  severe  or 
chronic  infections. 

The  general  plan  of  distribution  of  melanin  may  be  thus 
stated :  In  the  blood  current  it  may  exist  free  or,  more  com- 
monly, is  contained  within  the  phagocytes  and  the  red  cells 
infected  with  pigmented  parasites,  and  is  more  abundant  in 
the  capillaries  than  in  the  larger  vessels.  In  the  viscera  it  is 
oftenest  seen  in  the  spleen,  bone-marrow,  brain,  and  liver, 
especially  in  the  endothelial  cells,  but  in  the  spleen  and  bone- 
marrow  it  exists  also  outside  the  vessels  and  either  between 
or  within  the  cells  proper  to  these  tissues. 

The  distribution  of  the  parasites  varies  according  to  the 
type  of  the  attack;  it  has  been  shown  that  the  latter  depends 
largely  upon  the  localizations  of  the  parasites.  They  are  usu- 
ally abundant  in  the  splenic  blood  irrespective  of  the  form 
assumed  by  the  attack.  It  occasionally  happens  that  death 
supervenes,  notwithstanding  a  progressive  diminution  of  the 

174 


PLATE  VI 


■ 


J^&'-^r:, 


Slsr-.vS 

Fie.  i. 


!■*$* 


-?:■■■  ' . 

m^jm^WK  Mir 


JM:f 
i 

.  \       if ■ 


riS- 3-  Fig.  4. 

Fig.  1.  Liver  in  acute  malaria.     Fig.  2.  Pia  mater  in  acute  malaria.     Fig.  3.  Spl> 
in  acute  malaria.     Fig.  4.  Omentum  in  acute  malaria.     (Kelsch  and  Kiener. 


een 


PATHOLOGIC    ANATOMY  I75 

parasites,  so  that  the  latter  may  be  scanty  or  even  absent.  In 
the  spleen  are  found  not  only  schizonts,  but  also  numerous 
sexual  forms,  which  are  likewise  usually  found  in  the  bone- 
marrow  and  even  in  the  liver,  but  in  the  brain  gametes  are 
conspicuously  few.  Parasitic  development  is  checked  almost 
immediately  upon  the  death  of  the  host. 

The  spleen  is  always  more  or  less  enlarged,  though  perhaps 
slightly  so  in  acute  cases  following  recent  infection.  The  edges 
are  often  rounded,  the  organ  tending  to  lose  its  characteristic 
contour  and  to  assume  a  spheric  shape.  The  color  varies 
from  reddish  brown  to  almost  black,  being  darker  in  old 
malarials.  In  consistence  it  is  usually  softer  than  normal, 
often  semifluid,  sometimes  resembling  a  bag  of  pulp.  The 
capsule  is  thinned,  occasionally  adherent  to  the  adjacent 
organs,  and  is  very  liable  to  rupture.  The  cut  surface  is  dark 
in  proportion  to  the  age  of  the  infection.  The  pigmentation 
is  occasionally  uniform  and  the  tissues  hardly  distinguishable, 
though,  as  a  rule,  the  Malpighian  bodies  stand  out  distinctly. 
The  venous  sinuses  are  often  dilated.  Microscopically  there 
is  enormous  cellular  hyperplasia  with  distention  of  Mall's 
pulp  cords.  The  spleen  cells  are  everywhere  intercalated  with 
red  blood  corpuscles,  a  large  per  cent,  of  which  are  infected. 
The  parasites  may  be  in  the  same  or  in  different  stages  of 
development.  The  pigment  is  contained  in  the  large  mono- 
nucleated  leukocytes,  endothelial  cells,  and  giant  cells.  The 
latter  contain  also  red  cells,  parasites,  and  even  small  phago- 
cytes, and  are  most  abundant  in  the  splenic  vein.  They  some- 
times show  evidences  of  necrosis.  The  Malpighian  bodies 
and  the  fibrous  trabecular  are  usually  unpigmented.  Mitotic 
cells  may  be  found  in  the  pulp  and  in  the  Malpighian  bodies. 
The  circulation  may  be  so  obstructed  that  edema,  interstitial 
hemorrhage,  and  cellular  necrosis  may  occur. 

The  liver  is  generally  enlarged,  but  in  a  less  proportion  as 
to  frequency  and  size  than  the  spleen.  The  color  is  usually 
a  dirty  brown,  the  surface  is  sleek,  and  the  form  is  preserved. 
The  consistence  may  be  normal  or  somewhat  diminished.  The 
parenchyma  presents  a  reddish-brown  color  after  recent  in- 
fection and  the  cut  surface   drips   blood.     The  gall-bladder 


176  THE   STUDY  OF   MALARIA 

is  often  distended  with  a  quantity  of  dark,  inspissated  bile. 
Microscopically  parasites  are  not  so  abundant  as  in  the  spleen. 
Pigment  is  found  in  the  vessels,  especially  in  the  blood  capil- 
laries. Here  are  found  also  altered  parasites,  melaniferous 
leukocytes,  and  large  endothelial  cells  containing  coarse  grains 
of  pigment.  The  macrophages  are  sometimes  of  an  enormous 
size.  The  pigmented  endothelial  cells  are  swollen  and  the 
capillaries  are  not  infrequently  entirely  obstructed  with  pig- 
mented cellular  elements.  The  hepatic  cells  do  not  contain 
melanin,  but  are  frequently  charged  with  hemosiderin,  and 
may  show  evidences  of  cloudy  swelling,  atrophy,  or  necrosis. 
Karyokinesis  is  occasionally  noted.  Areas  of  focal  necrosis 
have  been  described. 

The  kidneys  on  gross  inspection  show  few  changes;  they 
may  be  slightly  enlarged  and  hyperemic.  Microscopic  exami- 
nation shows  a  marked  pigmentation  of  the  Malpighian  cor- 
puscles, together  with  degenerated  tubular  epithelium.  While 
the  epithelium  of  the  tubules  may  be  healthy,  it  often  shows 
cloudy  swelling  and  necrosis.  In  the  straight  tubules  there 
may  be  casts  of  various  sorts.  Melanin  is  found  in  the  glome- 
ruli, less  often  in  the  tubules.  The  cells  may  contain  hemo- 
siderin granules.  Parasites  are  rare  in  the  glomerular  ves- 
sels, but  may  be  found  in  the  intertubular  capillaries. 
Ewing's177  case  with  massing  of  the  parasites  in  the  renal 
capillaries  has  been  mentioned.  A  true  glomerulitis  has  been 
found  in  cases  of  the  algid  type. 

In  cerebral  cases  the  only  variation  from  the  normal  con- 
dition of  the  stomach  and  bowels  may  be  a  slight  pigmen- 
tation. In  fatal  cases  of  the  algid  and  choleraic  forms  the 
gastro-intestinal  tract  may  contain  a  bloody  fluid  and  the 
mucous  membrane  may  be  swollen,  hyperemic,  pigmented, 
necrotic,  or  ulcerated.  The  follicles  and  Peyer's  patches  may 
be  hypertrophied  and  prominent.  Microscopically  there  is 
vivid  injection,  parasitic  and  pigmentary  thrombosis  of  the 
capillaries,  hemorrhagic  points,  and  necrosis.  The  peritoneum 
is  usually  normal. 

Macroscopically  the  lungs  may  show  nothing  abnormal  save, 
probably,  slight  results  of  hypostasis,  which  in  some  cases  may 


PATHOLOGIC    ANATOMY  1 77 

be  cadaveric  lesions.  Occasionally  there  are  hemorrhagic 
areas.  Microscopically  neither  pigment  nor  parasites  are  so 
evident  as  in  certain  of  the  other  organs.  The  capillaries  are 
congested,  sometimes  thrombosed,  and  contain  infected  ery- 
throcytes, phagocytes,  which  often  show  signs  of  degenera- 
tion, and  macrophages.  The  capillary  epithelium  may  be  swol- 
len, but  is  only  occasionally  pigmented.  The  pleurae  show 
nothing  abnormal. 

The  heart  muscle  is  ordinarily  pale  and  flabby,  but  the 
muscular  fibers  do  not  usually  afford  degenerative  signs.  The 
capillaries  may  contain  parasites  in  greater  or  less  number,  and 
the  endothelium  may  be  swollen.  Cases  in  which  the  parasites 
are  very  numerous  in  the  cardiac  capillaries,  such  as  that  of 
Ewing,181  are  very  rare. 

In  cerebral  cases  the  meninges  of  the  brain  are  deeply 
hyperemic,  and  excess  of  serum  is  found  in  the  meshes  of 
the  pia,  in  the  ventricles,  and  at  the  base  of  the  brain.  The 
cerebral  substance  is  commonly  darkly  pigmented  and  con- 
gested, and  may  show  hemorrhages,  usually  punctiform,  occa- 
sionally larger.  The  hemorrhages  occur  oftener  in  the  cere- 
brum, but  may  be  present  in  the  cerebellum.  In  the  abdominal 
form  the  brain  may  show  but  few  pathologic  changes.  Micro- 
scopically in  the  cerebral  cases  the  capillaries  are  seen  to  be 
filled,  even  to  occlusion,  with  pigment,  parasites,  and  phago- 
cytes, the  latter  in  the  same  or  in  different  stages  of  schizo- 
gony; gametes  are  seldom  found.  In  some  instances  nearly 
every  red  cell  contains  one  or  more  parasites.  Localization  of 
parasites  are  found  not  only  in  the  cerebrum,  but  also  in  the 
cerebellum  and  medulla.  The  capillary  endothelium  may  be 
swollen,  pigmented,  and  undergoing  fatty  degeneration.  Sec- 
ondary changes,  such  as  perivascular  exudation,  hemorrhages, 
and  necrosis,  are  not  uncommon  results  of  thrombosis.  De- 
generative changes  in  the  ganglion  cells  have  been  detected. 

The  bone-marrow  is  of  a  dark  color  approaching  that  of 
the  spleen,  and  sometimes  diffluent.  Microscopic  examination 
reveals  hyperemia,  the  capillaries  being  engorged  with  pig- 
mented parasites  and  giant  cells  clinging  to  the  vessel  walls. 
The  parasites  exist  as  free  spores,  schizonts,  which  are  fre- 
12 


178  THE   STUDY   OF   MALARIA 

quently  sporulating,  and  gametes  in  large  numbers.     Extra- 
vascular  parasites  and  free  pigment  are  also  found. 

CHRONIC  MALARIA 

The  spleen  is  always  enlarged.  The  form  is  usually  pre- 
served. Its  average  weight  is  from  700  to  800  grams,  though 
it  may  attain  four  or  five  times  this  weight.  In  consistence 
it  is  usually  firmer  than  normal.  The  capsule  is  thickened, 
especially  at  the  convexity.  Upon  the  surface  are  scattered 
indurated  whitish  plaques  of  fibrous,  occasionally  calcareous, 
consistence,  evidences  of  perisplenitis.  Adhesions  to  the 
diaphragm  or  other  parts  are  not  infrequent.  Subcapsular 
infarcts  are  occasionally  encountered.  In  section  the  paren- 
chyma is  usually  found  firm,  only  rarely  is  it  of  diminished 
consistence.  The  color  varies  from  that  of  muscular  tissue  to 
slate  color.  The  thickened  trabecular,  like  white  bands,  are 
very  evident.  The  Malpighian  follicles  are  sometimes  con- 
spicuous, sometimes  indistinct.  In  old  cases  there  is  an  over- 
growth of  connective  tissue,  particularly  near  the  capsule.  His- 
tologically the  chief  changes  found  are  trabecular  hyperplasia 
and  venous  dilatation.  The  process  sometimes  resembles  a 
hypertrophic  cirrhosis.  The  fibrous  trabecular  are  hypertro- 
phied  and  there  is  formation  of  new  connective  tissue.  The 
venules  are  notably  dilated,  the  walls  thickened,  and  the  blood 
rich  in  pigmented  leukocytes  and  macrophages.  The  deposition 
of  pigment  is  in  general  similar  to  that  in  acute  malaria. 
There  is  at  times  little  change  in  the  lymphoid  tissue  forming 
the  arterial  sheaths  and  Malpighian  bodies,  but  this  may  be 
hyperplastic.  Necrosis  of  the  spleen  pulp  is  observed,  sur- 
rounded by  evidences  of  regeneration.  These  regenerative 
processes  consist  chiefly  of  increased  vascularization,  forma- 
tion of  connective-tissue  network  enclosing  giant  cells,  and 
hyperplasia  of  lymphoid  tissue  beginning  in  the  Malpighian 
bodies. 

The  liver  is  not  so  constantly  enlarged  as  is  the  spleen  and 
never  attains  so  excessive  a  degree  of  hypertrophy.  It  may 
weigh  from  2  to  4  kilograms.  In  rare  instances  it  is  atrophic. 
The  consistence  is  firm,  occasionally  somewhat  doughy.     The 


PLATE  vn 


|  r.   ...  !  __ 


m 

SUv, 


; 


Fig.  i. 


Figs,  i,  2 


PATHOLOGIC    ANATOMY  1 79 

capsule  is  tense  and  may  be  thickened.  There  may  be  present 
whitish  bands  or  patches,  the  results  of  perihepatitis.  The 
color  varies  from  reddish  to  almost  black.  The  cut  surface 
is  usually  found  to  be  congested  and  may  drip  with  blood.  The 
color  is  more  or  less  dark  red.  There  may  sometimes  be  de- 
tected on  gross  inspection  an  increase  of  connective  tissue. 
Microscopically  the  hepatic  cells  are  seen  to  be  hypertrophied 
and  hyperplastic,  showing  evidences  of  cloudy  swelling  and 
necrosis,  or  atrophied  as  a  consequence  of  vascular  dilatation. 
In  certain  areas  there  may  be  a  complete  disappearance  of 
hepatic  cells,  which  are  replaced  by  connective  tissue,  Kupffer's 
cells,  or  beginning  formation  of  new  hepatic  cells.  The  nuclei 
are  frequently  multiple,  and  when  single  may  be  much  larger 
than  normal  and  contain  one  or  two  nucleoli.  The  hepatic 
cells  may  be  charged  with  hemosiderin.  .  Pigment  is  contained 
in  the  endothelial  and  Kupffer's  cells,  especially  in  congested 
areas  and  in  the  periphery  of  the  lobule.  There  is  sometimes 
diffuse  overgrowth  of  connective  tissue.  The  blood  capillaries 
are  usually  dilated  and  congested  with  blood  rich  in  pigmented 
leukocytes;  the  circulation  is  commonly  sluggish.  The  bile 
capillaries  are  ordinarily  unaltered.  The  perivascular  lymph 
channels  may  be  dilated.  Amyloid  degeneration  beginning 
apparently  at  the  periphery  of  the  lobules  is  not  rare. 

The  kidneys  are  usually  increased  in  volume  and  in  weight. 
The  contracted  kidney  has  been  described  in  connection  with 
malaria,  but  there  is  some  doubt  as  to  the  etiologic  relation- 
ship. The  surface  of  the  kidney  is  smooth,  the  color  is  dark 
red,  and  the  consistence  is  slightly  increased.  Upon  section 
the  cortical  substance  is  reddish  gray.  The  pyramids  are 
markedly  hyperemic,  the  red  tint  being  most  decided  at  the 
border  of  the  pyramidal  substance.  Upon  microscopic  ex- 
amination the  convoluted  tubules  and  ascending  limb  of 
Henle's  loop  are  found  dilated.  The  epithelium  is  swollen, 
charged  with  hemosiderin,  and  may  be  undergoing  degenera- 
tion. In  the  collecting  tubules  the  epithelium  is,  as  a  rule,  only 
slightly  altered.  These  tubules  rarely  contain  granular  or 
hyaline  casts  or  desquamated  epithelium.  Bowman's  capsule 
presents  changes  similar  to  those  of  the  convoluted  tubules. 


l8o  THE    STUDY   OF   MALARIA 

The  renal  arterioles  are  congested  and  the  capillaries  are  dilated 
and  gorged  with  blood  rich  in  leukocytes,  more  marked  in  the 
pyramidal  than  in  the  cortical  substance.  Melanemia  is  not 
so  decided  in  the  kidney  even  when  profuse  in  the  spleen  and 
liver.  There  is  generally  little  change  in  the  connective  tissue. 
Here  and  there  is  a  slight  thickening  of  the  intertubular  con- 
nective tissue.  The  blood-vessels,  the  glomeruli,  and  the  walls 
of  the  renal  tubules  may  undergo  amyloid  degeneration.  This 
is  more  diffuse  in  the  kidneys  in  chronic  malaria  than  in  the 
other  organs. 

The  alimentary  tract  may  show  evidence  of  amyloid  de- 
generation in  the  stomach  or  bowel  and  dysenteric  lesions  in 
the  colon. 

In  the  lungs  may  be  pigmentation  and  anemia,  and  in  the 
pleural  cavity  an  effusion. 

The  heart  is  relaxed  and  often  dilated  and  sometimes  shows 
evidence  of  degeneration  of  the  musculature. 

The  bone-marrow  is  of  firmer  consistence  and  more  deeply 
colored  than  normal,  especially  toward  the  ends  of  the  long 
bones.  There  is  usually  a  decrease  of  fat  and  a  proliferation 
of  marrow  cells,  together  with  large  cells,  some  undergoing 
karyokinesis,  lymphoid  cells,  and  nucleated  red  cells.  The 
vessel  walls  are  thickened.  In  some  instances  there  is  atrophy 
of  the  bone-marrow. 

The  elimination  of  the  pigment  probably  consumes  three 
or  four  months  after  the  cessation  of  infection,  though  this 
varies  with  the  activity  of  the  eliminative  processes. 

HEMOGLOBINURIC  FEVER 
The  pathologic  findings  vary  in  proportion  to  the  proximity 
and  intensity  of  the  malarial  attack.  In  addition  to  the  changes 
characteristic  of  malaria  there  are  found,  in  blackwater  fever 
subjects,  the  results  of  hemoglobinemia  and  polycholia  chiefly 
in  the  kidneys  and  liver.  Occasionally  post  mortems  do  not 
reveal  malarial  evidences,  as  in  two  cases  reported  by  Curry,186 
but  this  is  very  exceptional.  The  body  is  usually  deeply  jaun- 
diced. There  may  or  may  not  be  edema.  The  muscular  sys- 
tem is  often  icteric. 


PLATE  VIII 


m 


Fig.  i. 


*X; 


sStefc 


Fig.  2. 
Fig.  i. — The  kidney  in  chronic  malaria  with  hemoglobinuria  fever. 
Fig.  2. — The  kidney  in  malarise  cachexia.     (Kelsch  and  Kiener.) 


PATHOLOGIC    ANATOMY  l8l 

The  spleen  is  enlarged,  often  enormously  so,  and  congested. 
The  surface  color  varies  from  grayish  to  reddish  brown,  almost 
black.  The  capsule  is  thickened  and  usually  strips  easily,  but 
may  be  adherent.  The  consistence  of  the  organ  is  often  so 
diminished  that  it  appears  like  a  pulpy  sac.  The  trabecular 
are  thickened  and  fibrous ;  the  pulp  is  decidedly  increased.  The 
Malpighian  corpuscles  are  usually  hypertrophied,  sometimes 
giving  the  appearance  of  sago  spleen.  Pigment  is  usually 
abundant.  It  is  contained  within  the  cells  or  lying  between 
them.  The  cells  of  the  Malpighian  bodies  show  the  greatest 
quantity  and  largest  masses.  The  large  mononuclear  cells  and 
giant  cells  are  pigmented.  The  leukocytes  lying  external  to 
the  walls  of  the  small  veins  may  show  more  pigment  than  those 
scattered  here  and  there  throughout  the  pulp.  The  color  of 
the  pigment  varies  from  yellow  to  almost  black,  and  may  con- 
sist of  hemosiderin  or  melanin.  The  walls  of  the  smaller 
vessels  are  thickened,  and  the  lumen  may  be  obliterated.  The 
sinuses  may  be  obliterated  with  pigmented  and  other  cells. 
The  endothelial  cells  may  be  proliferating,  and  often  contain 
granules  of  pigment.  Parasites  and  pigmented  leukocytes  may 
be  present  in  the  spleen  when  not  discoverable  in  the  general 
circulation.  There  may  be  round  cell  infiltration  around  the 
trabecular. 

The  liver  is  enlarged,  congested,  and  surcharged  with  bile. 
It  varies  in  color  from  a  decided  yellow  to  a  dark  brown.  The 
capsule  is  slightly  adherent.  The  surface  is  usually  smooth, 
but  there  may  be  subcapsular  nodules  from  the  size  of  a  pin- 
head  to  that  of  a  pea,  which  on  section  exude  a  thick,  cheesy 
matter.  There  is  abundant  pigmentation,  often  rod-shaped, 
especially  of  the  endothelial  cells,  macrophages,  and  leukocytes. 
The  course  of  the  capillaries  may  be  well  marked  by  the  pig- 
ment contained  in  the  endothelial  cells  and  that  between  the 
wall  and  the  adjacent  liver  cells.  Both  the  yellow  and  black 
pigments  are  found,  the  former  especially,  in  the  liver  cells. 
Pigmentation  is  often  more  pronounced  in  the  center  of  the 
lobule.  Thrombi  of  pigmented  cells  in  the  capillaries  and  sub- 
lobular  veins  occur,  with  cloudy  swelling  and  fatty  degenera- 
tion of  liver  cells.     These  retrogressive  processes  are  in  the 


l82  THE   STUDY   OF   MALARIA 

form  of  islands.  The  biliary  injection,  more  intense  in  the 
center  of  the  hepatic  lobule,  may  extend  to  the  smallest 
branches.  Regenerative  efforts  on  the  part  of  the  liver  cells 
are  very  much  more  common  than  in  pernicious  malaria  ( Mar- 
chiafava  and  Bignami).  Karyokinetic  barrels  and  manasters 
predominate.  This  is  interpreted  by  Bastianelli  as  evidence 
of  hyperfunction  of  the  liver.  Marchiafava  and  Bastianelli 
both  agree  in  believing  that  this  multiplication  of  the  hepatic 
cells  is  an  attempt  on  the  part  of  the  liver  to  meet  the  in- 
creased demands  for  work  in  eliminating  the  detritus  of  hemo- 
globin (Thayer).  The  gall-bladder  is  usually  distended  with 
bile. 

The  kidneys  are  generally  congested,  weigh  more,  and  are 
softer  than  normal.  The  capsule  is  loosely  attached.  On 
section  the  cortex  is  often  yellowish ;  the  pyramids  may  present 
brownish  streaks,  more  intense  toward  the  apices.  In  the 
cortex  may  be  found  wedge-shaped  hemorrhages  with  bases 
toward  the  capsule  and  apices  pointing  toward  the  medulla. 
The  medullary  pyramids  may  show  minute  hemorrhages.  The 
glomeruli  often  escape  undamaged;  there  is  rarely  any  pig- 
mentation of  the  cells  within  Bowman's  capsule ;  there  may  be 
cloudy  swelling,  and  slight  epithelial  desquamation.  The 
epithelia  of  the  convoluted  tubules  usually  show  cloudy  swell- 
ing, fatty  degeneration,  or  coagulation  necrosis.  There  may  be 
pigmentation  of  the  epithelial  cells.  The  lumina  are  often 
plugged  with  hemoglobin  casts  holding  the  epithelia  in  place. 
The  changes  in  the  straight  tubules  are  similar,  but  casts  are 
more  numerous.  The  epithelium  of  Henle's  loops  is  better 
preserved,  but  the  lumen  is  usually  choked  with  casts  of  hemo- 
globin and  epithelial  detritus  from  the  convoluted  tubules. 
Biliary  pigment  also  occurs  here.  Karyokinesis  is  sometimes 
seen  in  the  epithelium  of  Henle's  loops  and  of  the  convoluted 
tubules. 

The  stomach  and  intestines  may  be  negative.  The  serous 
coat  may  be  pale,  the  mucous  membrane  congested  and  bile- 
stained,  especially  near  the  opening  of  the  common  bile-duct. 
There  may  be  isolated  hemorrhages,  excoriations,  and  pigmen- 
tation.    The  pancreas  is  normal. 


FLATE  IX 


Fie.  i. 


» ,*■ 
> 

."'■•' 

K:'.'> 

:■> 

.A'  " 

"%  .■* 

j-V  '•* 

•%ts 

£ 

».-' 

f 

s    •• 

-"  .  . 

J  ff 

"•*  *  jfi*  i  -• ' 

•.-.- 

-•     • 

V 

... 

•• 

'•V 

:*  %  '• 

.♦.. 

j 

Fig.  2. 
The  kidneys  in  blackwater  fever  (Werner). 
Fig.  i. — Occlusion  of  the  straight  tubules. 
Fig.  2. — Iron  reaction  with  potassium  ferrocyanide. 


PLATE  X 


The  kidneys  in  blackwater  fever  (Werner). 
Fig.  i.— Degenerative  changes  in  the  epithelium  of  the  convoluted  tubules. 
Fig.  2. — Dilatation  of  the  lumen  of  the  convoluted  tubules. 


PLATE  XI 


Ficr.    !. 


Fis 


The  kidneys  in  blackwater  fever  (Werner). 
Fig-  T- — Different  characters  of  included  masses  in  the  glomeruli,  the  convoluted 

tubules,  the  straight  tubules,  and  the  intercalary  portion. 
Fig.  2. — Different  characters  of  coagula  in  the  ascending  and  descending  limbs 

of  Henle's  loops. 


PATHOLOGIC   ANATOMY  1 83 

The  pleurae  may  show  punctate  hemorrhages  and  the  cavity- 
may  contain  a  quantity  of  serous  fluid.  The  surface  of  the 
lungs  may  show  slaty  specks  and  striae.  The  cut  surface  is 
very  pale,  and  exudes  a  very  small  amount  of  very  pale,  frothy, 
serous  fluid.  There  may  be  an  ashy  discoloration  in  the  course 
of  the  vessels,  hypostatic  congestion,  and  edema. 

The  pericardium  may  contain  from  a  few  drams  to  several 
ounces  of  a  clear  or  sanguineous  fluid,  and  may  present  hemor- 
rhages varying  in  size  from  that  of  a  millet  seed  to  that  of  a 
cent.  The  heart  is  pale  and  often  flabby.  The  muscular 
fibers  are  easily  separable;  the  walls  may  be  very  thin.  The 
left  ventricle  is  usually  strongly  contracted,  the  right  collapsed. 
Auricles  and  ventricles  may  contain  coagula  or  thrombi. 
Microscopically  the  fibers  stain  well  and  show  striations  per- 
fectly; there  are  some  areas  of  slight  pigmentation  and  some 
of  connective-tissue  proliferation;  the  nerve  trunks  in  the 
transverse  section  show  marked  degeneration;  empty  nerve 
sheaths  are  seen,  and  some  connective-tissue  proliferation  into 
funiculus   (Goltman  and  Krauss). 

The  brain  is  usually  pale  and  unpigmented;  the  latter  ven- 
tricles may  contain  an  excess  of  fluid.  The  convexity  of  the 
pia  may  show  slight  cloudiness  in  the  course  of  the  vessels. 
The  puncta  vasculosa  may  be  scarcely  visible.  The  bone- 
marrow  shows  the  usual  changes  of  malaria.  Melanin,  hemo- 
siderin, and  proliferating  normoblasts  may  be  found. 


CHAPTER  V 

CLINICAL  HISTORY 

The  simplest  and  most  logic  classification  of  the  malarial 
fevers  is,  according  to  the  form  of  the  several  parasites  caus- 
ing them,  into  tertian,  quartan,  and  estivo-autumnal.  The  en- 
deavor to  affiliate  the  tertian  and  quartan  parasites  with  the 
intermittent  fevers  and  the  estivo-autumnal  with  the  remittent 
is  fruitless,  for  a  remittent  temperature  is  by  no  means  a 
characteristic  of  estivo-autumnal  infections.  Neither  is  the 
division  into  quotidian,  tertian,  and  quartan  consistent.  Quoti- 
dian paroxysms  may  be  due  to  estivo-autumnal  infection, 
double  tertian,  or  triple  quartan.  Tertian  paroxysms  may  be 
produced  by  estivo-autumnal  parasites  or  by  simple  tertian. 
The  three  forms  of  malaria  will  be  studied  in  their  acute  and 
chronic  courses,  larvated  or  masked  forms,  with  the  complica- 
tions and  sequelae. 

ACUTE  MALARIA 

Incubation. — The  period  of  incubation  varies  within  very 
wide  limits.  It  may  be  stated  as  a  general  proposition  that  the 
incubation  period  is  longest  in  quartan  infections  and  shortest 
in  the  estivo-autumnal.  The  average  period  is,  for  quartan, 
twelve  to  eighteen  days;  tertian,  six  to  fourteen  days,  and 
estivo-autumnal,  two  to  ten  days.  Much  longer  periods,  run- 
ning into  several  months,  have  been  reliably  recorded.  These 
must  be  regarded  as  cases  of  chronic  malaria  where  the  latent 
stage  precedes  the  active,  and  are  analogous  to  those  cases  of 
syphilis  in  which  the  secondary  manifestations  occur  without 
recognized  primary  lesion,  and  are  to  be  explained  satisfactorily 
only  by  parthenogenesis. 

General  Description  of  a  Malarial  Paroxysm. — The  forms 
of  acute  malaria  have  so  many  points  in  common  that  it  is 
convenient  to  describe  first  the  typic  malarial  paroxysm. 

184 


CLINICAL  HISTORY  1 85 

Prodomata  may  be  perceived  by  the  patient.  They  may 
correspond  to  the  last  few  parasitic  sporulations  preceding  that 
which  causes  the  paroxysms  or  may  occur  only  a  few  hours 
before  the  access.  They  are  ill-defined,  but  usually  consist  of 
languor,  anorexia,  headache,  aching  of  the  loins  and  hips, 
thirst,  epigastric  distress,  a  disposition  to  stretch  and  yawn, 
and  chilliness  along  the  course  of  the  spine.  These  symptoms 
may  be  so  slight  as  to  escape  attention.  The  typic  malarial 
paroxysm  comprises  three  well-marked  stages :  the  cold  stage, 
the  hot  stage,  and  the  sweating  stage. 

The  cold  stage  presents  itself  with  the  rapid  intensification 
of  the  prodromata  described.  The  sensation  of  coldness  spreads 
to  every  part  of  the  body.  The  skin  becomes  pale,  especially 
the  lips,  the  ears,  and  the  nails,  and  the  papillae  of  the  skin 
stand  out,  forming  the  so-called  "goose-skin."  The  patient 
shivers,  sometimes  so  violently  that  he  shakes  the  bed;  he 
covers  up,  his  teeth  chatter,  and  he  looks  and  feels  cold.  The 
slightest  motion  of  the  body  or  of  the  bedclothing  increases 
the  vehemence  of  these  phenomena.  Notwithstanding  these 
evidences  of  coldness,  the  thermometer  shows  an  elevation  of 
internal  temperature.  The  fever  may  even  precede  the  cold 
stage.  The  patient  complains  of  a  tight  headache,  a  backache, 
precordial  oppression,  and  dyspnea.  He  often  complains  of 
general  soreness,  as  severe  as  if  having  been  beaten.  He  may 
suffer  with  nausea  and  vomiting  of  bile.  There  is  apt  to  be 
frequent  micturition  of  small  quantities  of  limpid  urine.  The 
respiration  is  rapid  and  tremulous.  The  pulse  is  accelerated, 
diminished  in  volume,  and  increased  in  tension.  The  cold  stage 
may  last  from  a  few  minutes  to  two  or  three  hours. 

With  the  onset  of  the  hot  stage  hot  flashes  alternate  with 
cold  until,  the  sense  of  heat  becoming  general,  the  patient 
presents  a  very  different  picture  from  that  of  the  first  stage. 
He  begins  to  uncover,  the  skin  is  flushed  and  hot,  the  pulse 
full  and  bounding,  the  respiration  deeper,  and  the  urine  is 
scanty  and  high  colored.  There  may  be  constipation  or 
diarrhea.  The  tongue  is  coated,  bulky,  and  usually  shows 
indentations  produced  by  the  teeth.  Herpes  appears  upon  the 
lips  or  nose.    The  spleen  is  enlarged  and  the  upper  half  of  the 


i86 


THE   STUDY  OF  MALARIA 


abdomen  is  tender  on  pressure.  The  headache,  soreness, 
nausea,  and  vomiting  continue,  there  is  often  great  thirst  and 
epigastric  pain,  and  the  temperature  continues  to  rise. 

When  the  temperature  is  at  its  height  the  sweating  stage  is 
ushered  in  by  crisis.  Beads  of  perspiration  begin  to  appear 
upon  the  face,  then  a  universal  sweat  breaks  out,  and  the  skin, 
which  was  first  cold  and  rough,  then  hot  and  dry,  now  becomes 
moist  and  natural.  The  temperature  falls  to  normal,  often  a 
little  below;  the  pulse  and  respiration  resume  their  normal 


"— ■ 

tu 

< 

U 

0. 

in 

H 

m.  m. 

300 

290 

280 

270 

260 

250 

240 

230 

220 

210 

200 
190 
180 
170 

440 

DAY  OF 

DISEASE 

DAY  OP 
MONTH 

HOUR. 

:ent. 
41°— 

40»— 

39»— 

3S°— 

370— 

38»— 

FAH. 

106° 

105* 

1040 

103° 

102° 

101° 

100* 

090 

980 

970 

969 

i 

Y\ 

'. 

'■ . 

j 

| 

\x.  ■ 

~. 

.' 

:"' 

1 

'■ 

'■ 

; 

,: 

y 

; 

.:_ 

** 

V 

A:.. 

K 

r^ 

■■'-  ■■ 

Fig.  51. — Single  tertian  infection. 

features.  The  soreness  disappears,  the  thirst  ceases,  and  the 
patient  often  feels  so  comfortable  that  he  takes  a  short  nap. 

Such  is  the  typic  procession  of  one  of  the  most  remark- 
able events  in  the  category  of  disease.  The  conspicuous 
changes,  the  swift  succession  of  stages,  and  the  punctual  pe- 
riodicity of  paroxysms  are  unparalleled  in  pathology. 

In  some  paroxysms,  however,  one  or  two  stages  may  be 
missing.  The  temperature  may  rise  unaccompanied  by  a  cold 
stage  or  may  fall  to  normal  unattended  by  sweats.  This  con- 
stitutes the  so-called  dumb  chill.  The  cold  stage  is  the  least 
constant,  the  hot  stage  the  most  so.     The  cold  stage  is  most 


CLINICAL   HISTORY 


187 


constant  in  quartan  fever,  least  so  in  estivo-autumnal  infec- 
tions. 

Simple  Tertian  Infection. — Infection  with  a  single  brood 
of  simple  tertian  parasites  causes  a  paroxysm  every  other  day. 
The  parasites  being  in  the  same  stage  of  development  causes 
great  regularity  in  the  course.  From  the  beginning  of  one 
paroxysm  to  the  beginning  of  another  is  almost  precisely  forty- 
eight  hours.  When  the  interval  is  not  quite  so  long,  as  some- 
times happens,  the  paroxysms  are  said  to  anticipate;  when 


Fig.  52. — Double  tertian  infection. 

longer,  as  is  more  rarely  the  case,  they  are  said  to  postpone  or 
to  retard.  Postponing  is  usually  regarded  as  evidence  of  abat- 
ing activity. 

In  more  than  half  the  simple  tertian  cases  the  infection  is 
double ;  that  is,  there  are  two  distinct  generations  of  parasites. 
These  generally  mature  on  alternate  days;  two  paroxysms  on 
one  day  with  an  intervening  day  of  apyrexia  being  extremely 
rare.  The  paroxysms  may  occur  at  the  same  time  every  day 
and  be  similar  in  every  respect.  Usually,  however,  there  is  a 
perceptible  difference  between  the  paroxysms  of  successive 
days,  a  difference  consisting  of  time  of  onset,  severity,  and 


1 88  THE   STUDY   OF   MALARIA 

relative  length  of  the  stages  of  the  paroxysms.  It  very  rarely 
happens  that  the  paroxysms  are  so  lengthened,  and  one  so 
anticipates  that  its  onset  occurs  during  the  latter  stage  of  the 
preceding  paroxysm.    They  are  styled  subintrant  attacks. 

A  change  of  type  from  quotidian  to  tertian  paroxysms,  or 
vice  versa,  is  commonly  observed.  The  change  from  quotidian 
to  tertian  may  be  spontaneous  or  the  result  of  incomplete  medi- 
cation or  improvement  in  hygienic  conditions,  one  group  of 
parasites  perishing.     A  change  from  tertian  to  quotidian  may 


a 

% 

Hi 

300 
290 
280 
270 
260 

aso 

240 
230 
220 
210 
200 
190 
180 
170 
160 

DAY  CF 
DISEASE, 

— 

DAY  OP 

MONTH 

HOUR. 

410— 

40»— 
390- 
38°- 
3?o_ 
36«- 

FAH. 

106° 
105° 

104» 

103° 
102« 
101° 
1000 
99° 
98° 
97o 
960 

il 

:l 

: 

• 

: 

i 

I 

... 

p* 

Y\ 

r 

■U 

Vs 

Fig-  53- — Single  quartan  infection. 

occur  without  apparent  cause  or  following  indiscretions  of 
various  sorts. 

The  onset  is  probably  more  common  during  the  morning, 
but  this  is  neither  constant  nor  of  diagnostic  dignity.  The 
invasion  is  almost  always  with  a  chill.  The  temperature  rises 
suddenly  and  falls  likewise.  Commonly  there  are  no  grave 
symptoms,  but  a  mild  delirium  is  not  rare.  The  temperature 
usually  goes  as  high  as  103°  to  105°  F.  The  average  duration 
of  the  paroxysm  is  from  eight  to  twelve  hours. 

During  apyrexia  the  patient  may  feel  perfectly  well  except 
slight  weakness,  headache,  or  vertigo.     He  is  usually  able  to 


CLINICAL   HISTORY 


189 


attend  to  his  duties.  The  tendency  to  spontaneous  cure  is 
greater  than  in  either  of  the  other  forms  of  malaria,  the  attack 
not  infrequently  subsiding  after  a  number  of  paroxysms,  with- 
out any  medication  or  with  only  a  purgative. 

Quartan  Infection. — The  quartan  parasite  accomplishes  its 
endogenous  cycle  in  seventy-two  hours.  Hence  infection  with 
a  single  generation  of  quartan  parasites  produces  a  paroxysm 
followed  by  two  days  of  apyrexia  and  a  second  paroxysm  on 
the  fourth  day.  Such  attacks  are  popularly  known  in  the  South 
as  "third-day  chills."    A  double  quartan  infection  reverses  the 


< 

a 

EU 
& 

m.  at. 

300 

290 
280 
270 
260 
2S0 
240 
230 
220 
210 
200 
190 
180 
170 

m 

DAY  OF 
DISEASE 

DAY  OP 
MONTH 

MOOR. 

PS555T 

41°— 
40°— 
39°- 
33°- 
37°— 
36°- 

FAH. 

106° 

10S» 

1040 

103« 

1020 

101° 

100° 

99° 

98° 

970 

96° 

J    : 

1    ■ 

! 

;. 

! 

1  ; 

3\  ■ 

n 

1    : 

• 

V 

f 

1 

V  1 

1 : 

1 

1 

•\ 

• 

M 

i\ 

-M 

hr 

S- 

: 

i 

Fig.  54. — Double  quartan  infection. 

course,  causing  two  paroxysms  on  successive  days,  followed 
by  a  day  of  apyrexia.  Triple  quartan  infections,  the  parasites 
maturing  on  successive  days,  give  rise  to  quotidian  fever.  As 
in  simple  tertian  intermittents,  quartan  accesses  sometimes 
anticipate  or  retard.  Subintrance  in  triple  infections  is  rarely 
seen,  due  probably  to  the  shorter  duration  of  the  paroxysms. 
Changes  of  type  between  single,  double,  and  triple  quartan  are 
sometimes  observed. 

The  onset,  especially  in  single  infections,  occurs  probably 
more  often  during  the  afternoon  hours.     The  symptoms  are 


190 


THE    STUDY    OF   MALARIA 


those  of  the  typic  paroxysm  and  are  well  marked.  The  cold 
stage  is  not  only  more  constant  than  in  the  other  forms,  but  is 
more  intense  and  usually  of  longer  duration.  The  three  stages 
are  sharply  contrasted.  Pernicious  symptoms  are  very  rarely 
observed  in  connection  with  quartan  infections.  This  may  be 
accounted  for  by  the  more  equal  distribution  through  the  circu- 
lation of  the  parasites  which  show  no  tendency  to  congregate, 
and  by  the  longer  apyrexial  periods  between  the  paroxysms. 
The  average  duration  of  the  paroxysm  is  eight  or  ten  hours. 


— 

w 

a. 

S 

(U 
H 

300 
290 
280 
270 
250 
250 
240 
230 
220 

210 

200 

190 

180 

170 

160.. 

'  DAY  OF 

DISEASE 

OAY  OP 

MONTH 

HOUR. 

:ent. 
41«— 

40<>_ 

39«— 
3S»- 
370— 
36»- 

FAH. 
106P 

105° 

ID*8 

103° 
102" 
101° 
100° 
990 

93° 
970 

96° 

•• 

1 

: 

h 

■  1 

;< 

n 

r 

[!, 

i 

J 

:j 

: 

1 

i 

i 

\f 

■ 

i 

i 

f 

■ 

■ 

1 

1 

i 

% 

-r 

-r 

k 

1 

!• 

Ir 

k 

W 

V? 

-  r; 

: 

; 

•fig-  55- — Triple  quartan  infection. 

The  obstinate  disposition  of  quartan  fever  to  recur  has  been 
a  matter  of  common  knowledge  for  centuries,  and  is  still  a 
popular  idea.  This  may  doubtless  be  accounted  for  at  this  day 
by  the  probability  that,  owing  to  the  greater  interval  between 
the  accesses,  the  specific  is  not  properly  taken.  Most  physicians 
will  agree  that  quartan  fever  is  just  as  amenable  to  appropriate 
therapy  as  the  other  acute  forms.  As  in  tertian  fever,  an 
almost  complete  feeling  of  well  being  may  be  experienced  be- 
tween paroxysms,  the  patient  usually  being  able  to  attend  to 
business. 

Estdvo-autumnal  Infection. — The  chief  feature  of  infec- 


CLINICAL    HISTORY 


I9I 


tion  with  estivo-autumnal  parasites  is  the  irregularity  of  the 
course  as  contrasted  with  that  of  tertian  and  quartan  infec- 
tions. A  classification  is  difficult  and,  while  that  into  estivo- 
autumnal  or  malignant  tertian  and  quotidian  is  perhaps  best, 
these  may  be  clinically  indistinguishable. 

Malignant  Tertian. — This  form  of  infection  is  due  to  para- 
sites which  tend  to  mature  in  forty-eight  hours.  It  is  character- 
ized by  a  long  paroxysm  and  a  short  apyrexia.  The  duration 
of  the  access  is  from  twenty-four  to  forty-eight  hours  or  more. 


m,  m. 

300 

290 
280 
270 
260 
250' 
240 
230 
220 
210 
200 
190 
180 
170 
160 

DAY  OP 

DISEASE 

01 

H 
< 

a. 

DAV  OP 

MONTH 

HOUR. 

;ent. 
41<>— 

40»— 

39»— 

38°- 

37°— 

36°— 

FAH. 

106° 
105° 
104° 
103° 
102° 
101° 
1Q0° 
990 

98° 
970 

96° 

ft 

\ 

l\ 

I 

I 
I 

\H 

v] 

1 

I 

I 

w 

: 

-i 

If 

f- 

r 

If 

/ 

•f- 

: 

i 

MM 

Fig.  56. — Tertian  estivo-autumnal  malaria. 

Anticipation  and  subintrance  are  oftener  observed  here  than 
in  any  other  form  of  malaria. 

Prodromal  symptoms  are  usually  pronounced.  The  cold 
stage  is  often  not  manifest;  the  sweating  stage  is  less  com- 
monly missing.  The  typic  temperature  is  characteristic.  It 
rises  abruptly,  often  as  high  as  104°  F.  On  reaching  its 
height  it  remits  with  slight  oscillations  for  a  few  hours.  It 
then  makes  a  marked  remission  and  again  rises  suddenly,  usu- 
ally higher  than  before.  The  final  fall  is  by  crisis.  It  is  cus- 
tomary, following  Marchiafava  and  Bignami,  to  divide  this 
course  into  five  stages :  1,  the  rise  of  invasions,  the  fastigium; 


192 


THE   STUDY   OT  MALARIA 


3,  the  pseudocrisis ;  4,  the  precritical  rise;  5,  the  crisis.  This 
curve  is  simulated  only  by  simple  tertian  fever  with  subintrant 
attacks,  which  is  uncommon.  Unfortunately  this  typic 
sequence  is  far  from  constant;  the  modifications  are  very 
numerous  and  are  too  irregular  to  analyze. 

The  symptoms  of  the  hot  stage  are  more  pronounced  than  in 
the  infections  previously  described.  The  headache  and  back- 
ache are  worse,  the  general  depression  is  more  profound,  stupor 
and  delirium  may  appear,  and  pernicious  symptoms  may  arise. 
During  the  short  interval  the  patient  does  not  regain  his  ease 


57. — Quotidian  estivo-autumnal  malaria. 


as  in  the  simple  intermittent  fevers,  but  the  aching  and  pros- 
tration continue,  and  he  may  be  unaware  that  the  fever  has 
left 

Quotidian. — The  quotidian  estivo-autumnal  fever  is  more 
regular  in  its  course  than  the  tertian,  especially  at  first,  though 
there  is  nothing  characteristic  in  the  temperature  curve,  which 
may  closely  resemble  a  double  tertian  or  a  triple  quartan. 
Later  it  is  apt  to  lose  some  of  its  regularity  by  anticipation 
or  by  lengthening  of  the  paroxysms,  whose  average  duration 
is  from  six  to  ten  hours.     The  chill  is  rather  more  constant 


CLINICAL    HISTORY  193 

than  in  the  tertian,  otherwise  the  symptoms  are  identical,  the 
patient  not  regaining  strength  from  one  paroxysm  to  another. 
In  the  interval  the  temperature  is  prone  to  sink,  even  as  low 

as  to  950  F. 

Mixed  Infections. — Infections  with  two  or  more  species  of 
the  malarial  parasite  are  known  as  mixed  or  combined  infec- 
tions. The  most  frequent  combination  is  of  simple  tertian 
and  estivo-autumnal.  As  a  rule,  one  parasitic  form  predomi- 
nates and  produces  its  usual  picture;  this  may,  however,  be 
considerably  modified  by  the  other  group  of  parasites.  The 
most  frequent  modification  in  the  temperature  chart  is  a  tend- 
ency to  continuity.  The  paroxysms  are  not  usually  as  typic 
as  in  simple  infections  and  are  not  so  regular  in  their  occur- 
rence. 

Analysis  of  Symptoms. — Temperature. — The  main  char- 
acteristics of  malarial  temperature  have  been  given  when  treat- 
ing- of  the  several  forms.  It  remains  only  to  consider  a  few 
general  traits. 

The  feature  of  the  temperature  in  uncomplicated  and  un- 
treated malaria  is  periodicity.  The  temperature  is,  in  a  great 
majority  of  instances,  intermittent.  The  fever  of  longest 
intervals,  the  quartan,  has  only  one  mode  of  causation,  the 
quartan  parasite.  The  fever  of  next  longest  intervals  between 
times  of  onset,  the  tertian,  has  two  modes,  the  simple  tertian 
parasites  and  the  tertian  estivo-autumnal;  while  the  fever  of 
shortest  intervals,  the  quotidian,  may  be  due  to  triple  quartan, 
double  tertian,  or  quotidian  estivo-autumnal  infection.  As 
intimated,  quotidian  fever  may  change  to  a  single  or  double 
quartan  or  to  a  tertian,  and  both  tertian  and  quartan  may 
become  quotidian,  but  tertian  fever  never  becomes  quartan,  or 
vice  versa,  without  reinfection. 

In  tertian  and  quartan  infections  the  temperature  usually 
rises  rapidly  after  the  onset,  reaching  the  acme  during  the 
second  stage  of  the  paroxysm  and  declining  during  the  third 
to  normal  or  a  little  below  normal.  This  is  also  the  usual 
course  in  quotidian  estivo-autumnal,  the  temperature  chart 
showing  symmetric  ascent  and  descent,  producing  an  arrow- 
head appearance.     In  this  infection  the  temperature  descends 

13 


194  THE   STUDY   OF  MALARIA 

rather  lower  during  the  fever-free  interval  than  in  the  others. 
The  typic  run  of  tertian  estivo-autumnal  has  been  given  as 
follows :  i,  the  stage  of  initial  ascent;  2,  the  fastigium,  during 
which  the  temperature  may  show  fluctuations  of  a  half  degree 
to  a  degree;  3,  the  pseudocrisis ;  4,  the  precritical  or  final 
ascent;  and,  5,  the  crisis. 

Continued  temperature  in  malaria  is  not  as  common  as  usu- 
ally regarded ;  remittent  fever  was  formally  thought  to  be  the 
rule  in  the  summer-autumn  malarial  fevers.  The  causes  of 
this  error  are  three ;  first,  in  tertian  estivo-autumnal  infections 
the  apyretic  interval  is  short;  secondly,  this  interval  often 
occurs  during  the  night  or  early  morning  hours;  thirdly,  the 
patient,  guided  by  the  discomfort  which  continues  during  the 
interval  usually  denies  that  he  has  been  free  from  fever. 
Nevertheless,  a  continued  temperature  is  occasionally  noted 
in  malaria,  especially  in  tertian  estivo-autumnal  infections.  It 
may  be  regularly  remittent  or  may  be  irregular.  The  follow- 
ing are  the  chief  causes  of  a  continued  malarial  temperature : 

1.  Prolongation  of  the  paroxysms. 

2.  Anticipation  of  the  paroxysms. 

3.  Infection  with  more  than  one  brood  of  the  same  species 
of  parasite. 

4.  Infection  with  more  than  one  species. 

5.  Complications. 

So-called  spontaneous  recovery  may  occur  in  either  form  of 
malaria.  As  a  rule,  the  recovery  is  only  temporary  and  is 
merely  the  transition  from  the  active  to  the  latent  stage,  re- 
lapses usually  occurring  sooner  or  later.  Favorable  hygienic 
conditions  encourage  spontaneous  cure. 

The  duration  of  untreated  acute  malaria  is  too  indefinite 
to  permit  of  exact  statements.  While  simple  tertian  may 
terminate  after  a  few  paroxysms,  an  estivo-autumnal  fever 
may  continue  three  or  four  weeks  if  it  does  not  in  the  mean- 
time become  pernicious. 

A  postmalarial  secondary  fever,  or  spodogenous  fever,  is 
occasionally  observed  after  the  infection,  particularly  estivo- 
autumnal,  has  lasted  for  some  time.  It  persists  for  days  or 
weeks  uninfluenced  by   quinine.      The  blood   examination   is 


CLINICAL   HISTORY  1 95 

negative  for  parasites.  Resorption  of  debris,  toxins,  and  vis- 
ceral lesions  have  been  offered  as  explanations  of  this  process, 
but  none  of  these  are  entirely  satisfactory. 

Circulatory  System. — The  Blood. — The  blood,  being  the 
habitat  of  the  parasites,  furnishing  their  pabulum,  containing 
their  toxin,  besides  carrying  one  of  the  host's  mechanism  of 
defense  against  their  depredations,  shows  important  changes. 

The  volume  of  the  blood  as  a  whole  is  somewhat  diminished. 
The  specific  gravity  is  only  slightly  lowered,  and  usually  only 
in  recent  infections,  the  destruction  of  the  solid  elements  being 
nearly  compensated  by  the  excretion  of  fluids.  The  density, 
at  first  lowered,  approaches  normal  as  the  infection  persists. 
The  experiments  that  have  been  performed  with  reference  to 
the  tonicity  of  the  blood  in  malaria  have  uniformly  shown 
that  this  is  increased.     . 

The  parasites  of  malaria  have  a  very  unequal  distribution, 
some  being  almost  constantly  found  in  the  superficial  circula- 
tion throughout  their  asexual  cycle,  others  only  during  the 
early  stages  of  their  development,  modestly  retiring  to  the 
recesses  of  the  viscera  for  procreation.  The  organisms  are 
sometimes  scanty  in  the  peripheral  blood,  occasionally  entirely 
absent. 

The  tertian  parasite,  more  abundant  in  the  deep  circulation, 
may  be  observed  in  the  peripheral  circulation  throughout  the 
course  of  the  asexual  cycle,  excepting  the  sporulating  forms, 
which  are  only  exceptionally  seen.  The  gametes  are  not  in- 
frequently detected. 

The  quartan  parasite  is  most  evenly  distributed,  being  about 
equally  common  in  the  visceral  and  superficial  blood.  Fur- 
thermore, all  stages  of  the  asexual  development,  including 
the  sporulating  forms,  may  be  followed  in  blood  obtained 
from  the  peripheral  circulation.  Quartan  gametes  are  rarely 
seen. 

The  estivo-autumnal  parasites  are  seen  in  only  the  earliest 
phases.  In  some  localities  the  gametes  are  very  commonly  ob- 
served after  the  infection  has  persisted  a  week  or  more;  in 
others,  even  where  severe  infections  of  long  standing  are  en- 
countered, they  are  more  rarely  noted. 


196  THE   STUDY  OF  MALARIA 

Pigment  is  most  frequently  contained  within  the  large  mono- 
nuclear, less  often  the  polymorphonuclear,  leukocytes,  but  may 
exist  free  in  the  blood  current.  It  is  of  a  dark  reddish-brown 
or  black  color,  and  occurs  as  granules,  rodlets,  or  irregular 
clumps. 

One  of  the  best-known  facts  in  the  study  of  malaria  is  the 
rapid  and  widespread  destruction  of  the  red  blood-cells.  A 
certain  number  of  erythrocytes  perish  with  each  parasitic 
sporulation  like  soldiers  after  a  volley  from  the  enemy.  It  is 
not  uncommon  for  a  fourth  to  a  half  million  red  cells  per 
cmm.  to  be  destroyed  during  each  of  the  first  two  or  three 
paroxysms,  and  this  may  progress  until  the  count  is  consider- 
ably less  than  one  million  per  cmm.  As  a  rule,  in  uncompli- 
cated benign  malaria  this  erythrorrhexis  is  greater  during  the 
early  paroxysms,  diminishing  with  each  successive  paroxysm, 
the  cells  apparently  requiring  some  sort  of  immunity.  It  is 
likewise  usual  for  the  marked  early  destruction  to  be  rapidly 
compensated,  or  nearly  so,  by  the  activity  of  the  blood-forming 
organs.  Later  it  is  more  difficult  for  these  organs  to  replace 
even  the  smaller  number  of  destroyed  cells.  Hence  the  anemia 
is  commonly  in  proportion  to  the  severity  and  duration  of  the 
attack.  Restitution  of  the  red  cells  is  more  rapid  and  certain 
with  tertian  and  quartan  than  with  estivo-autumnal  infections. 
Race,  age,  and  constitution  are  also  factors  in  the  rapidity  of 
reconstruction. 

There  are  certain  changes  that  occur  in  the  infected  cells 
which  should  be  mentioned.  The  cells  containing  the  simple 
tertian  parasites  are  swollen  and  somewhat  decolorized.  Those 
containing  the  quartan  parasites  are  shrunken  and  somewhat 
darker  in  color.  The  cells  harboring  estivo-autumnal  organ- 
isms have  the  appearance  of  old  gold  or  of  brass,  and  become 
somewhat  smaller.  A  curious  appearance  of  some  infected 
cells  is  what  has  been  termed  stippling.  This  may  be  seen  in 
both  simple  tertian  and  estivo-autumnal  infections,  but  presents 
features  more  or  less  characteristic  in  each.  In  simple  tertian 
the  dots  are  fine  and  abundant.  In  estivo-autumnal  they  are 
coarse,  irregular,  maybe  cleft-like,  and  few  in  number — from 
two  to  six.      The   fine   stippling  of  tertian  infection  is   also 


CLINICAL    HISTORY  1 97 

known  as  "Schuffner's  dots."  Stippling  is  brought  out  by 
staining. 

A  mysterious  property  of  infected  cells  is  their  apparent 
tendency  to  mutual  attraction.  For  instance,  it  is  very  common 
to  observe  under  the  microscope  two  or  more  infected  cells  in 
juxtaposition,  even  where  these  are  the  only  infected  cells  in 
the  field.  This  property,  whatever  be  its  nature,  probably 
explains  the  parasitic  localizations  in  pernicious  attacks. 

Changes  occur  also  in  non-infected  cells.  The  commonest 
of  these  are,  in  my  experience,  in  the  order  named :  the  occur- 
rence of  macrocytes  and  microcytes,  polychromatophiles,  and 
poikilocytes.  Nucleated  reds  are  occasionally  observed.  Baso- 
phile  granulation  is  sometimes  noted.  It  was  this  lesion  which 
Plehn  formerly  mistook  for  the  latent  phase  of  the  parasite. 
These  granules  appear  in  a  varying  number  of  cells,  occa- 
sionally in  those  containing  parasites,  as  minute  dots  or  streaks 
from  one-quarter  to  one-half  micron  in  diameter.  When  few 
in  number  they  appear  coarser.  They  stain  best  with  the 
Romanowsky  class  of  stains.  Basophile  granulation  is  not 
characteristic  of  malaria,  but  is  found  in  a  number  of  affec- 
tions. Retraction  of  hemoglobin  and  vacuolization  are  com- 
mon findings  in  malarial  blood. 

The  hemoglobin  generally  falls  decidedly.  Its  curve  is  apt 
to  run  parallel  with  and  a  little  below  that  of  the  red  cells,  and 
is  slower  in  returning  to  normal.  The  hemoglobin  content  is 
no  guide  as  to  the  severity  of  the  disease. 

The  leukocytes  are,  in  benign  malaria,  usually  slightly  dimin- 
ished. A  leukocytosis  is  found  only,  in  pernicious  malaria  or 
in  association  with  complications.  The  differential  formula  is 
the  most  noteworthy  feature.  Its  peculiarity  is  the  large 
mononuclear  increase.  Bastianellr33  observed  a  diminution  of 
the  polymorphonuclears  and  increase  of  the  large  mono- 
nuclears, especially  in  advanced  and  pernicious  cases,  and  less 
marked  during  the  early  paroxysms.  Billings280  noted  a  great 
absolute  and  relative  increase  of  the  large  mononuclears,  a 
decided  diminution,  both  relatively  and  absolutely,  of  the  poly- 
morphonuclears, a  wide  variation  of  small  mononuclears,  and 
a  slight  diminution  of  eosinophiles.      Stephens  and  Christo- 


I98  THE   STUDY   OF  MALARIA 

phers57  have  recorded  that  there  is  no  increase  of  the  large 
mononuclears  during  pyrexia,  but  that  the  increase  is  pro- 
nounced in  the  apyretic  interval,  or  immediately  following  the 
rise  of  temperature,  if  only  one  such  occurs.  They  also  noted 
that  in  certain  cases  this  change  was  extraordinarily  marked, 
the  large  mononuclears  during  the  interval  even  exceeding  in 
number  the  polymorphonuclears.  They  observed  further  that 
in  some  cases  the  mononuclear  increase  was  to  be  detected  even 
during  the  fever  stage,  but  in  these  cases  it  was  still  further 
evident  during  the  interval.  Rogers44  concludes  that  the  mono- 
nuclear increase  is  decidedly  more  marked  and  frequent  in 
benign  than  in  malignant  tertians.  He  accounts  for  this  by 
the  shorter  apyretic  interval  of  the  latter.  Krauss281  believes 
that  it  is  not  so  much  the  absolute  increase  of  the  large  mono- 
nuclear elements  as  the  relative  increase  over  the  small  lympho- 
cytes, which  is  characteristic  of  malaria.  Ziemann48  states  that 
in  the  beginning  of  the  access  there  is  often  a  transient  poly- 
morphonuclear leukocytosis,  which  recedes  during  the  acme  of 
the  fever  simultaneous  with  a  relative  increase  of  the  large 
mononuclears,  which  may  reach  15  per  cent,  or  more. 

Eosinophilia,  in  the  writer's  experience,  denotes  complica- 
tions, ordinarily  intestinal  helminthiasis. 

Billings'280  16  cases  showed  the  following  average: 

Per  cent. 

Small  mononuclears 16.9 

Large  mononuclears 16.9 

Polymorphonuclears    65.04 

Eosinophiles 0.96 

Krauss'281  204  cases : 

Per  cent. 

Small    lymphocytes 14.8 

Large    lymphocytes 19.5 

Polymorphonuclears    63.7 

Eosinophiles     2.0 

Rogers44  found  that  the  large  mononuclear  leukocytes  num- 
bered : 

0-8  per  cent,  in 6  cases 

8-12  per  cent,  in 10  cases 

12-15  per  cent,  in 25  cases 

15-20  per  cent,  in 16  cases 

Over  20  per  cent,  in 20  cases 


CLINICAL    HISTORY  1 99 

The  leukocytes  occasionally  undergo  degenerative  changes, 
among  which  are  fatty  degeneration  and  vacuolization  of  the 
protoplasm  and  fragmentation  and  chromatolysis  of  the 
nucleus. 

The  blood  platelets  are  somewhat  increased  in  malaria,  espe- 
cially during  the  interval  following  a  severe  attack. 

The  carefully  conducted  experiments  of  Capograssi84  tend 
to  show  that,  while  malarial  blood  possesses  agglutinative 
properties,  it  is  of  no  diagnostic  importance. 

Celli,  Carducci,  and  Casagrandi,147  investigating  together, 
were  unable  to  determine  definitely  the  existence  of  an  hemo- 
lysin, but  concluded  that  such  a  body  probably  existed.  Later 
Casagrandi  was  able  to  verify  the  presence  of  an  hemolysin 
in  malarial  blood,  and  concluded  that  it  was  masked  by  an 
antibody.  De  Blasi82  found  in  a  watery  solution  of  centrifu- 
gated  red  cells  antihemolytic  action  in  15  cases  out  of  19.  The 
4  negative  cases  were  in  chronic  malarias  who  had  been 
under  the  influence  of  quinine  a  long  time.  This  hemolytic 
action  is  not  specific  for  malaria,  occurring  in  measles,  typhus, 
erysipelas,  and  scarlatina,  but  not  in  healthy  persons. 

At  the  height  of  the  fever  the  pulse  may  reach  130  or 
more.  During  the  interval  it  usually  becomes  almost  quite 
normal  in  tertian  and  quartan  infections.  In  estivo-autumnal 
fever  it  depends  upon  the  severity  of  the  attack  and  the  resist- 
ance of  the  patient.  Occasionally  the  rapidity  of  the  pulse  does 
not  show  the  usual  relation  to  the  height  of  the  temperature, 
but  may  be  below  100,  with  high  fever.  This  is  sometimes 
observed  during  the  attack,  but  is  rather  more  common  during 
convalescence.  During  the  cold  stage  of  the  paroxysm  the 
blood  pressure  rises  decidedly,  falling  during  the  second  stage, 
to  become  normal  in  the  sweating  stage.  This  is  fairly  con- 
stant, variations  being  due  not  to  a  difference  of  parasites, 
but  to  individual  conditions.  An  anemic  murmur  may  be  heard 
over  the  heart.  A  sense  of  precordial  oppression  or  acute  pain 
are  common  complaints. 

Respiratory  Organs. — Respiration  is  usually  accelerated  in 
proportion  to  the  temperature.  Cough  is  a  frequent  symptom. 
In  children  a  frequently  repeated  superficial  hacking  cough  is 


200  THE   STUDY   OF   MALARIA 

often  an  indication  of  nausea.  Bronchial  catarrh  is  not  infre- 
quently observed,  accompanied  by  sibilant  rales  on  ausculta- 
tion. Epistaxis  may  occur  and  is  occasionally  alarmingly  pro- 
fuse. 

G 'astro-intestinal  Organs. — While  the  paroxysm  is  on,  the 
appetite  is  usually  completely  lost.  In  tertian  and  quartan 
malaria  this  may  be  regained  during  the  interval,  but  in  estivo- 
autumnal  anorexia  generally  persists  throughout  apyrexia.  The 
patient  ordinarily  complains  of  a  bitter  taste  in  the  mouth  and 
fulness,  discomfort,  or  pain  in  the  epigastric  region.  The 
tongue  is  large,  flabby,  thickly  coated,  usually  anemic,  and 
showing  the  prints  of  the  teeth  along  the  edges.  Nausea  is 
nearly  a  constant  symptom,  and  retching  and  vomiting  are  dis- 
tressing. The  vomitus  consists  of  matters  ingested,  bile,  or 
slimy  mucus.  The  bowels  are  constipated,  regular,  or  loose,  in 
the  order  of  frequency  named;  choleraic  or  dysenteric  dis- 
charges occasionally  appear.  More  or  less  enlargement  of  the 
spleen  is  a  usual  occurrence,  together  with  pain  and  tenderness 
in  the  left  hypochondrium.  In  primary  acute  infections  the 
enlargement  may  not  be  prominent;  in  later  infections  the 
spleen  is  often  palpable  beyond  the  costal  margin.  The  spleen 
is  rarely  much  enlarged  in  the  negro.  Enlargement  of  the  liver 
is  much  less  constant  and  less  marked  than  splenic  hypertrophy. 
There  usually  exists  tenderness  in  the  epigastric  and  right 
hypochondriac  regions. 

Genito-urinary  Organs. — Urine. — As  a  general  rule,  the 
urine  emitted  during  a  cold  stage  is  paler  in  color  and  that  of 
the  stage  of  fever  highly  colored,  but  individual  circumstances 
may  produce  numerous  exceptions  to  this  rule.  In  certain 
cases  of  estivo-autumnal  fever  the  urine  may  be  very  highly 
colored  and  contain  a  heavy  deposit.  In  these  cases  the  urine 
contains  biliary  coloring  matters  and  an  excess  of  urobilin. 
The  diazo  reaction  sometimes  obtains.  The  indican  is  fre- 
quently increased.  In  tertian  and  quartan  cases  the  quantity 
of  the  urine  is  somewhat  augmented,  in  estivo-autumnal  dimin- 
ished. Polyuria  of  tertian  and  quartan  malaria  and  that  occur- 
ring sometimes  in  estivo-autumnal  occurs  under  two  conditions, 
the  polyuria  of  the  paroxysm  and  that  of  convalescence  or  post- 


CLINICAL    HISTORY  201 

malarial  polyuria.  In  the  former  case  the  increase  in  the  quan- 
tity of  urine  excreted  coincides  nearly  with  the  paroxysm,  the 
amount  diminishing  during  the  interval.  The  polyuria  of 
convalescence  ordinarily  begins  from  three  to  six  days  after 
the  attack  and  continues  for  a  few  days  to  several  weeks.  The 
reaction  is  acid,  varying  directly  with  the  concentration  of  the 
urine.  The  specific  gravity  does  not  always  bear  a  definite 
relation  to  the  amount  of  the  urine,  as  might  be  inferred,  but 
may  be  relatively  high  when  the  urine  is  abundant,  or  low  with 
scanty  urine. 

The  output  of  urea  is  increased.  The  increase  begins  sev- 
eral hours  before  the  attack,  attains  its  maximum  toward  the 
end  of  the  cold  stage,  declining  to  or  below  normal  at  the  end 
of  the  paroxysm.  A  curious  fact  noted  by  Ringer  and  by 
Senator227  is  that  when  the  return  of  the  attack  has  been  pre- 
vented by  the  administration  of  quinine,  there  is  still  to  be 
observed  an  increase  in  the  excretion  of  urea  on  the  days  upon 
which  the  paroxysm  should  have  occurred. 

The  uric  acid  content  of  the  urine  is  only  slightly,  if  at  all, 
modified.  The  amount  of  chlorides  runs  parallel  with  the 
quantity  of  urine.  The  phosphates  are  eliminated  in  quantities 
less  than  normal  during  the  fever,  and  in  greater  quantities 
during  apyrexia.  The  entire  twenty-four-hour  urine  com- 
monly shows  an  increase.  The  variations  in  the  excretion  of 
the  sulphates  are  similar  to  those  in  regard  to  urea. 

The  elimination  of  the  sodium  and  potassium  bases  is  very 
inconstant,  both  as  to  quantity  and  as  to  the  stage  of  the  disease 
during  which  elimination  takes  place.  Malarial  urine  contains 
an  excess  of  iron,  especially  after  the  paroxysm.  It  is  de- 
pendent upon  and  proportionate  to  the  destruction  of  erythro- 
cytes. 

The  occurrence  of  albumin  in  the  urine  is  relatively  infre- 
quent in  the  mild  attacks  of  simple  intermittent  which  ter- 
minate after  one  or  two  paroxysms.  In  severe  estivo-autumnal 
infections,  however,  it  is  exceedingly  frequent.  Its  frequency 
varies  not  only  with  the  type  and  severity  of  the  attack,  but 
also  with  locality  and  other  circumstances.  The  following 
reports  are  tabulated  to  show  the  extent  of  these  differences, 


202  THE   STUDY   OF  MALARIA 

the  denominator  indicating  the  number  of  cases  of  malaria, 
the  numerator  the  number  in  which  albumin  was  found : 

Costa79   J  2 

F.    Plehn5 X 

Marchoux96 JJ}. 

Borne90 3.8% 

Thayer  and  Hewetson29 |f  f 

Solon86   2?% 

Schoo90 2% 

Thayer282   ff* 

Anders283   T^f7 

Atkinson285    TVT 

Chamberlain43 Tf-<j- 

Frerichs61    f$ 

Cook285  rffc 

Marchiafava  and  Bignami22  say  that  albuminuria  is  rare  in 
their  experience,  though  Kelsch  and  Kiener178  hold  the  opposite 
view,  and  Craig70  states  that  it  occurs  in  a  majority  of  the 
severe  cases. 

An  increased  toxicity  of  the  urine  has  been  found  in  large 
per  cent,  of  cases  of  malaria,  greatest  during  apyrexia  and  usu- 
ally intensifying  with  each  successive  paroxysm.  Brousse86 
arrived  at  the  following  conclusions :  1.  The  urotoxic  coefficient, 
calculated  by  means  of  the  formula  of  Bouchard,  the  average 
coefficient  being  .464,  rises  during  the  attack,  and  the  physio- 
logic effects  observed  are  those  usually  noted  after  the  injec- 
tion of  urine ;  dyspnea,  miosis,  fall  of  temperature,  exophthal- 
mia,  besides  convulsions.  2.  This  toxicity  is  diminished  during 
the  period  of  convalescence  from  the  intermittent  fevers  very 
much  below  that  of  the  urine  during  the  access,  and,  further- 
more, more  feeble  than  that  of  normal  urine. 

Nervous  System. — Headache  is  one  of  the  most  invariable 
symptoms  of  malaria.  Backache  and  somatic  soreness  are 
severe.  Sometimes  hyperesthesia  is  seen.  Vertigo  is  the  rule, 
especially  when  the  patient  is  upright.  Neuralgia,  facial  or 
intercostal,  is  a  not  infrequent  symptom.  Stupor  and  delirium 
are  present  in  grave  cases,  particularly  in  children. 

Skin. — During  the  first  stage  of  the  paroxysm  the  skin  is 
blanched  and  cold,  during  the  second  stage  hot,  dry,  and  per- 
haps turgid,  during  the  third  bathed  with  sweat,  becoming 
natural  toward  apyrexia.    Icterus  is  not  a  pronounced  symptom 


CLINICAL    HISTORY  203 

in  acute  cases  except  in  certain  pernicious  forms.  With  the 
possible  exception  of  pneumonia  herpes  is  seen  more  frequently 
in  malaria  than  in  any  other  disease.  Its  commonest  sites  are 
the  lips  and  nose,  but  it  may  appear  elsewhere.  It  is  not  nearly 
so  common  in  the  negro  as  in  the  white.  Urticaria  and 
erythema  are  sometimes  observed. 

PERNICIOUS  MALARIA 

Malaria  threatens  or  destroys  life  through  its  inherent  dan- 
gers, acutely  expressed,  through  the  sequelae  of  chronic  mani- 
festations, or  through  complications  in  any  stage.  Pernicious 
malaria  is  that  form  of  malaria,  extremely  acute,  which,  inde- 
pendently of  complications,  endangers  life  in  a  few  hours  or 
a  few  days.  This  gravity  may  be  due  to  the  intensification  of 
ordinary  malarial  symptoms  or  to  the  advent  of  unusual  ones. 
It  should  be  clearly  understood  that  pernicious  fever  is  not  a 
pathologic  entity,  but  is  a  form  of  malaria  from  the  simple 
modes  of  which  it  sometimes  differs  only  in  degree.  Its  patho- 
genesis is  intimately  associated  with  the  life  history  of  the 
malarial  parasite,  much  more  so  than  is  hemoglobinuric  fever. 
Intermediate  forms  may  be  encountered  which  may  be  difficult 
to  place,  as  cases  with  slight  somnolence,  abundant  sweats,  or 
cold  surface. 

Though  the  pernicious  forms  of  malaria  were  alluded  to 
by  Hippocrates  and  by  Celsus,  they  did  not  receive  any  de- 
tailed consideration  until  1743,  when  Torti  described  them. 
This  pyretologist  divided  the  pernicious  fevers  into  solitaries, 
those  characterized  by  the  continuity  or  acuteness  of  the  ordi- 
nary symptoms,  and  the  comitate?,  in  which  one  grave  symptom 
predominated.  The  comitates  he  subdivided  into  the  colliqua- 
tive, including  the  choleraic,  dysenteric,  atrabiliary,  cardialgic, 
and  diaphoretic,  and  the  coagulative,  including  the  syncopal, 
algid,  and  lethargic  forms. 

Alibert,  in  1804,  distinguished  twenty  varieties  of  pernicious 
malaria. 

Roux,  following  Jaccoud's  classification,  looks  on  all  as 
originating  in  the  vasomotor  and  sympathetic  systems  or  in 
the  cerebrospinal  system. 


204  THE   STUDY   OF   MALARIA 

Kelsch  and  Kiener  adopt  Torti's  system  with  slight  modifica- 
tions. 

Marchiafava  and  Bignami  arrange  the  pernicious  forms,  ac- 
cording to  the  course  of  temperature,  into  tertian,  quotidian, 
subcontinuous,  and  larval. 

Manson  groups  them  roughly  into  cerebral — including  the 
hyperpyrexia!,  comatose,  convulsive,  and  paretic  forms — and 
algid,  including  the  syncopal,  choleriform,  dysenteric,  and 
hemoglobinuric  forms. 

Dantec  classifies  the  varieties  anatomically  according  to  the 
organs  which  bear  the  brunt  of  the  attack,  namely :  ( i )  The 
brain,  (2)  the  medulla,  (3)  the  spinal  cord,  (4)  the  heart,  (5) 
the  lungs,  and  (6)  the  digestive  tube. 

Homem  describes  fifteen  definite  forms,  besides  several  un- 
defined varieties. 

Cardamatis  distinguishes  seventeen  varieties. 

More  than  thirty  so-called  varieties  of  pernicious  malaria 
have  been  described.  A  partial  list  of  these  includes  the  apo- 
plectic, ataxic,  comatose,  sudoral  or  diaphoretic,  delirious, 
eclamptic  or  convulsive,  tetanic,  typhoid,  amaurotic,  aphasic, 
ardent,  exanthematous,  hemiplegic,  hydrophobic,  neuralgic, 
cerebromeningeal,  cardialgic,  dyspenic  or  asthmatic,  pneumo- 
nic, pleuritic,  syncopal,  hemoptoic,  algid,  choleraic,  dysenteric, 
gastric  or  gastralgic,  hemorrhagic,  bilious  or  hepatic,  lymphatic, 
rheumatic,  and  nephritic  forms. 

This  multiplicity  is  due  to  two  causes :  first,  the  fanciful  and 
unnecessary  subdivision  of  typic  forms ;  second,  the  mistaking 
of  complications  for  true  pernicious  attacks. 

Any  classification  is  not  absolutely  essential,  and  all  are  more 
or  less  arbitrary.  Nevertheless,  for  convenience,  all  forms  of 
true  pernicious  malaria  may  be  easily  and  logically  arranged 
into  (1)  cerebrospinal,  (2)  thoracic,  and  (3)  abdominal  forms. 

Cerebrospinal  Forms. — The  representative  type  of  cerebro- 
spinal pernicious  malaria  is  the  comatose  variety,  which  is,  as 
well,  the  most  frequent  of  all  varieties. 

Comatose  malaria  may  make  its  appearance  as  the  first  mani- 
festation of  malaria  or,  more  commonly,  after  the  lapse  of 
one  or  more  paroxysms,  typic  or  irregular.     Violent  head- 


CLINICAL    HISTORY 


205 


ache,  stupid  countenence,  and  somnolence,  interrupted  by  fre- 
quent sighing,  with  a  mild  grade  of  mental  aberration  and  de- 
fective articulation  and  vision,  are  not  uncommon  prodomata. 
These  may,  however,  be  so  slight  as  to  escape  notice.  The 
onset  of  cerebral  symptoms  may  be  with  violent  abruptness 
(the  apoplectic  form  of  some  writers)  or,  as  is  most  common, 
begins  within  a  few  hours  after  the  commencement  of  the 
paroxysm    with    somnolence,    which    gradually    deepens    into 


••rffi 

MJg£ 

« n 

1*1 

,7B 

%m 

-W4f:  ; 

iW& 

lllllllllllllllii; 

1  ill  iiiiiii 

Fig.  58. — Comatose  malaria  ;  recovery. 

stupor  and  coma.  It  has  occasionally  happened  that  malarial 
coma  has  come  on  during  natural  sleep,  the  condition  of  the 
patient  being  discovered  by  accident.  Convulsions  may  precede 
the  coma,  especially  in  children,  or  there  may  be  extreme  rest- 
lessness, gritting  the  teeth,  and  jactitation.  The  cerebral  symp- 
toms may  vary  from  the  marked  drowsiness  to  profoundest 
coma.  The  eyes  may  be  closed  or  open  (coma-vigil).  The 
pupils  are  usually  equal  and  dilated  or  contracted,  but  may  be 


206  THE   STUDY   OF   MALARIA 

unequal  and  may  or  may  not  react  to  light.  Strabismus  is  an 
occasional  symptom.  The  face  is  congested  in  individuals  re- 
cently attacked  or  pallid  in  older  sufferers.  The  skin  is  at 
first  hot  and  dry,  perhaps  slightly  jaundiced;  later  it  may  be 
bathed  with  sweat.  Petechias  are  occasionally  seen.  Trismus 
may  be  present,  but  the  extremities  are  usually  completely  re- 
laxed, though  sensation  and  motion  are  often  not  entirely  abol- 
ished, as  sometimes  evidenced  by  resistence  to  hypodermic 
medication.  Cases  manifesting  muscular  rigidity  and  tonic 
contractures  have  been  reported  by  Schellong92  and  by 
Brown.286  Hyperesthesia  and  muscular  tremors  are  not  infre- 
quently present.    The  reflexes  may  be  increased  or  diminished. 

There  may  be  twitching  of  the  muscles  of  the  face,  usually 
confined  to  one  side.  Loud  calls  may  not  elicit  response,  and 
shaking  only  groans  and  unintelligible  utterances.  The  coma 
may  be  intermittent,  running  parallel  with  the  temperature. 
The  fever  in  most  cases  varies  from  101°  to  103"  F.,  but 
may  be  subnormal  or  hyperpyrexial.  The  pulse  is  at  first 
full  and  bounding,  later  small,  rapid,  and  feeble.  Dilation 
of  the  right  side  of  the  heart  may  exist  and  an  anemic  mur- 
mur may  sometimes  be  heard.  The  respiration  may  be  quiet, 
slow  or  rapid,  or  blowing  and  stertorous,  with  Cheyne- Stokes 
characteristics  late  in  the  course.  Edema  of  the  lungs  is  an 
occasional  late  occurrence.  Nausea  and  vomiting  are  seen 
early  in  the  attack,  if  they  are  present  at  all.  The  mouth 
and  tongue  are  dry,  the  latter  deeply  coated.  Herpes  and 
sordes  are  sometimes  noted.  Hiccough  is  an  occasional  symp- 
tom. The  tongue  when  protruded  may  be  drawn  to  one  side. 
In  cases  of  recent  infection  the  spleen  may  be  only  slightly  or 
not  at  all  enlarged;  in  other  cases  it  may  be  greatly  enlarged, 
constituting  a  valuable  diagnostic  sign. 

The  liver  may  be  tender,  but  is  usually  not  much  enlarged. 
The  evacuations  of  bowels  and  bladder  may  be  involuntary  or 
there  may  be  retention  of  urine.  The  bowels  are  often  con- 
stipated. 

In  favorable  cases  the  coma  gradually  fades,  consciousness 
slowly  dawns,  the  temperature  drops  to  or  below  normal,  the 
pulse  regains  its  normal  characteristics,  and,  save  the  physical 


CLINICAL   HISTORY  207 

weakness  and  a  degree  of  mental  hebetude,  all  is  well  with 
the  patient. 

In  unfavorable  cases  the  coma  becomes  absolute,  the  pulse 
becomes  rapid,  thready,  and  irregular,  the  breathing  is  stertor- 
ous and  of  Cheyne-Stokes  type,  tracheal  rattling  appears,  the 
face  becomes  cyanotic,  and  death  ensues  from  convulsions  or 
from  collapse. 

The  duration  of  an  attack  is  from  a  few  hours  to  a  few 
days. 

Hertz183  speaks  of  cases  of  "apparent  death"  arising  in  the 
course  of  comatose  attacks.  He  describes  these  cases  as  fol- 
lows: 

"Under  this  form  of  pernicious  intermittent  must  also  be 
classed  those  cases  of  apparent  death  which  may  last  from 
half  an  hour  to  four  hours.  Persons  subject  to  such  attacks 
may  remain  entirely  conscious,  seeing  and  hearing  everything 
that  occurs  or  is  said  around  them,  but  unable  to  move  or  to 
utter  a  sound ;  or  they  may  be  entirely  unconscious,  respiration 
arrested,  pulse  and  heart  beat  not  to  be  recognized,  and  even 
the  sharpest  irritants  applied  to  the  body  calling  forth  no  signs 
of  life  until,  at  the  beginning  of  the  sweating  stage,  the 
patient  comes  to  himself  and  the  various  organs  again  slowly 
manifest  their  activity.  Trousseau  reports  the  case  of  a  man 
who  had  had  fainting  fits  on  two  occasions  in  Algiers,  and  in 
a  subsequent  attack  fell  into  this  condition  of  simulated  death. 
It  was  not  until  he  had  been  carried  into  the  post-mortem  room 
that  evidences  of  life  were  observed  about  him,  whereupon  he 
was  returned  to  his  bed  and  recovered  under  quinine  treat- 
ment." 

Relapses  may  occur  after  the  apparently  favorable  deferves- 
cence of  the  symptoms.  Laveran1  saw  three  successive  attacks 
in  a  soldier.  Colin86  reports  several  examples  of  pernicious 
attacks  assailing  the  same  subject  repeatedly  at  intervals  of 
fifteen  to  twenty  days.  Mayer  states  that  in  a  third  of  the 
cases  another  attack  supervened  in  eight  or  ten  days.  More 
than  three  are  very  rare,  but  Homem157  records  the  case  of  a 
young  student  who  died  after  having  six  pernicious  paroxysms. 
It  has  long  been  maintained  that  the  third  attack  is  fatal.     It 


208  THE   STUDY   OF   MALARIA 

usually  holds  true  that  the  successive  paroxysms  increase  in 
severity  and  danger  to  the  patient.  In  the  interval  the  patient 
may  be  apathetic  or  may  complain  of  headache.  The  relapse 
may  appear  in  the  form  of  a  different  type  of  pernicious 
paroxysm,  as  algid  or  choleraic,  but  such  cases  are  very  rare. 

As  intimated,  the  apoplectic  form  of  pernicious  malaria  is 
merely  a  fulminant  variety  of  comatose  malaria.  In  these  rare 
cases  the  onset  is  equally  as  sudden  as  in  cerebral  hemorrhage, 
whence  the  name.  Laveran,1  Cardamatis287  and  Crespin144  are 
inclined  to  doubt  the  existence  of  this  variety,  but  cases  have 
been  reported  by  Morris,288  Davidson,66  Maurel,75  and  others. 
Ewing's  case  is  remarkable.  ''The  patient,  while  sitting  up  in 
bed  smoking,  three  times  in  five  days  suddenly  became  uncon- 
scious, his  pipe  fell  to  the  floor,  and  he  remained  stuporous 
for  three  or  four  hours.  At  the  end  of  that  period  he  would 
wake  up,  at  once  pick  up  his  pipe,  and  resume  smoking." 

Symptoms  originating  from  the  cerebellum  are  present  in 
rare  instances.  Such  are  slow,  monotonous  speech,  drowsiness, 
severe  depression,  and  incoordination  of  voluntary  movements. 

Marchiafava  and  Bignami22  describe  as  follows  the  interest- 
ing bulbar  symptoms  which  occasionally  present  themselves : 
"When  a  physician  unexpectedly  encounters  this  disease  he  is 
easily  inclined  at  the  first  glance  to  think  that  the  case  is  one 
of  a  patient  with  bulbar  paralysis  who  has  become  infected 
with  malaria,  but  this  suspicion  disappears  after  a  careful  ex- 
amination and  after  seeing  the  gradual  resolution  of  the  symp- 
toms. The  chief  symptoms  are  :  Difficulty  in  articulation,  which 
may  even  reach  anarthria;  a  weak  and  nasal  voice;  inferior 
facial  paralysis,  often  of  one  side  only;  a  half-open  mouth  from 
which  drools  the  saliva;  a  pendent  lower  lip;  a  dry  and  only 
slightly  movable  tongue;  difficult  or  abolished  deglutition.  If 
the  attack  tends  to  a  fatal  issue  we  have  the  added  symptoms 
of  sopor,  a  thready  intermittent  pulse,  labored  and  stertorous 
breathing,  and  clammy  sweat.  When,  however,  the  result  is 
favorable  the  patient  recovers  from  the  more  severe  symptom 
as  soon  as  the  fever  falls ;  the  bulbar  symptoms  usually  persist 
for  some  days,  although  in  milder  form,  and  then  gradually 
disappear,  the  dysphagia  going  first,  then  the  dysarthria  and 


CLINICAL    HISTORY  2CX) 

nasal  voice,  and  the  paresis  of  the  lower  part  of  the  face.  Two 
or  three  weeks  may  elapse  before  resolution  is  complete.  If 
the  malarial  infection  has  not  been  properly  treated  we  shall 
have  an  exacerbation  or  even  a  return  of  the  bulbar  symptoms 
in  the  relapses.  With  these  symptoms  there  are  sometimes 
associated  disturbances  of  equilibrium  which  recall  the  stagger- 
ing gait  of  cerebellar  disease." 

Cases  in  which  hemiplegia  occurs  have  sometimes  been  de- 
scribed as  the  hemiplegic  form  of  pernicious  malaria;  cases 
with  aphasia  as  the  aphasic  form.  These  two  are  not  infre- 
quently associated.  Paraplegia  is  a  very  rare  development  in 
pernicious  malaria. 

A  mild  delirium  is  frequently  present  in  the  cerebrospinal 
forms  of  pernicious  malaria.  When  it  is  conspicuous  it  forms 
the  so-called  delirious  type.  In  this  probably  more  than  in 
any  other  form  do  predispositions  have  a  causal  part,  espe- 
cially alcoholism,  nervous  predisposition,  mental  fatigue,  and 
exposure  to  solar  heat.  Delirium  in  this  condition  may  vary 
from  quiet  to  maniacal.  Cases  resembling  rabies  have  been 
designated  Intermittens  hydrophobica,  and  are  thus  described : 
"Violent  maniacal  delirium,  with  a  frequent  pulse,  red  glowing 
face,  and  clonic  spasms  of  the  muscles  of  deglutition  on  drink- 
ing or  even  at  the  sight  of  water;  these  spasms  then  pass  to 
the  muscles  of  the  face,  the  eyes,  and  the  neck,  and  finally  to 
those  of  the  entire  body,  a  disposition  to  bite  being  at  the  same 
time  developed."183 

Convulsive  or  eclamptic  pernicious  malaria  is  a  variety  of 
the  comatose  type  in  which  convulsions  are  a  prominent  feature. 
It  is  especially  common  in  children.  The  convulsions  may  be 
confined  to  certain  muscle  groups  or  may  be  general.  In  one 
of  my  cases  the  little  patient  had  twelve  convulsions  in  an  hour. 
Epileptiform  convulsions  have  been  described,  but  it  is  probable 
that  most  of  these  cases  are  complicated  with  true  epilepsy,  as 
the  case  of  Marchiafava  and  Bignami.162 

Cases  in  which  the  symptoms  resemble  more  or  less  closely 
those  of  tetanus  constitute  the  tetanic  type  of  some  writers. 
These  cases  are  said  to  have  been  relatively  frequent  in  the 
French    campaign    in    Madagascar.226      Ziemann48    records    a 

14 


2IO  THE   STUDY   OF   MALARIA 

typic  case.  The  most  prominent  symptoms  are  usually  tris- 
mus and  opisthotonos;  emprosthotonos  and  pleurosthotonos 
are  but  rarely  observed. 

Occasionally  amaurosis  arises  in  the  course  of  a  comatose 
attack.  It  may  be  transient  or,  in  rare  instances,  permanent. 
In  the  only  case  occurring  under  my  observation  vision  began 
to  improve  at  the  end  of  the  attack,  but  was  not  fully  restored 
until  after  several  weeks.  According  to  Poncet,101  the  per- 
sistence of  amblyopia  in  these  cases  is  due  to  optic  neuritis, 
peripapillary  edema,  extravasation  of  leukocytes,  plugging  of 
retinal  and  choroidal  vessels  by  parasites  or  pigmented  leuko- 
cytes, and  consequent  multiple  hemorrhages. 

A  rare  form  of  pernicious  malaria,  the  ataxic,  has  been 
described,  particularly  by  Angellini  and  Torti.67  The  prin- 
cipal symptoms  are  scanning  speech,  dysarthria,  weakness  of 
lower  limbs,  vertigo,  unsteady  gait  with  a  disposition  to  fall 
forward,  muscular  tremors,  and  exaggerated  reflexes.  Maurel75 
records  22  cases,  but  it  appears  that  some  of  these  cases  at 
least  do  not  belong  to  the  ataxic  type. 

Manson59  thus  describes  the  so-called  ardent  fever :  "In  the 
course  of  what  seemed  to  be  an  ordinary  malarial  attack,  the 
body  temperature,  instead  of  stopping  at  104°  or  105°  F., 
may  continue  to  rise,  and,  passing  107°  F.,  rapidly  mount  to 
uo°  or  even  to  112°  F.  The  patient,  after  a  brief  stage  of 
wild,  maniacal,  or  perhaps  muttering  delirium,  becomes  rapidly 
unconscious,  then  comatose,  and  dies  within  a  few  hours  or 
perhaps  within  an  hour  after  the  onset  of  the  pernicious  symp- 
toms." Both  the  cases  of  this  type  observed  by  Homem157 
ended  fatally. 

Typhoid  pernicious  has  been  most  carefully  studied  by  Bil- 
let.151 In  these  cases  the  clinic  picture  is  almost  identical  with 
that  presented  in  typhoid  fever.  The  temperature  is  periodi- 
cally intermittent  or,  as  is  more  common,  remittent,  and  usu- 
ally ranges  from  ioi°  to  103°  F.,  but  may  reach  106°  F. 
There  are  headache,  backache,  rapid  pulse,  torpid  digestive 
tract,  sordes,  splenomegaly,  apathy,  and  stupor.  There  may 
be  diarrhea  or  constipation,  and  bilious  vomiting  occurs  in 
some  cases.     The  abdomen  is  usually  tympanitic  and  there 


CLINICAL   HISTORY  211 

may  exist  tenderness  and  gurgling  in  the  right  iliac  fossa. 
Epistaxis  is  frequent.  Incoherent  speech,  delirium,  and  incon- 
tinence of  urine  and  feces  are  symptoms  of  severe  cases.  All 
of  Billet's  40  cases  showed  the  presence  of  malarial  parasites 
and  a  large  mononuclear  leukocytosis,  and  an  absence  of  rose 
spots  and  the  Widal  reaction.  The  average  duration  was  four 
or  five  days. 

Thoracic  Forms. — The  immunity  of  the  organs  of  the  chest 
to  localizations  of  the  malarial  parasites  and  to  the  effects  of 
their  toxins  is  remarkable.  Indeed,  the  thoracic  forms  are 
much  rarer  than  the  records  would  import,  for  the  older 
writers  especially  were  prone  to  attribute  any  complication  that 
might  present  itself  to  the  effect  of  the  mysterious  malarial 
poison. 

Ewing179  has  minutely  recorded  a  case  in  which  the  autopsy 
showed  an  enormous  number  of  parasites  in  the  capillaries  of 
the  heart  muscle.  The  symptoms  referable  to  the  heart  were 
feeble  pulse,  124  to  the  minute,  and  very  feeble  heart  sounds 
on  auscultation.  The  patient  was  comatose.  Benvenuti179  has 
reported  a  case  in  which  the  capillaries  of  the  myocardium, 
brain,  and  kidney  were  filled  with  infected  red  cells.  The  prin- 
cipal symptoms  were  coma  and  dyspnea.^ 

Formerly  cases  of  pneumonic  pernicious  malaria  were  more 
frequently  reported  than  at  present.  Since  more  exact  methods 
of  observation  have  come  into  use  it  is  certain  that  many  of 
these  cases  were  complicating  lobar  pneumonias.  That  the 
malarial  parasite  is  unable  to  cause  true  inflammation  of  lung 
tissue  is  now  widely  recognized,  and  was  maintained  by 
Colin,233  Jaccoud,289  Roux,m  and  Marchiafava  and  Bignami.102 
Nevertheless,  grave  symptoms  referable  to  the  lung,  and  more 
or  less  resembling  pneumonia,  may  arise  in  malarial  infections. 
Laveran,1  who  doubts  the  existence  of  a  pneumonic  pernicious, 
admits  that  in  certain  patients  attacked  with  intermittent  fever 
there  may  be  observed,  with  each  attack,  pulmonary  conges- 
tion, accompanied  with  subcrepitant  rales,  which  may  lead  to 
a  belief  in  the  existence  of  a  pneumonic  intermittent.  Bacelli 
proved  the  existence  of  a  group  of  cases  nearly  resembling 
pneumonia    in    symptomatology.      The    characteristic   cough, 


212  THE   STUDY   OF  MALARIA 

dyspnea,  and  pain  in  the  side  are  present.  There  may  be 
moderate  dulness  and  coarse,  sonorous,  and  sibilant  rales 
heard  over  the  portion  of  the  lung  involved.  Other  writers 
describe  intermittent  lung  symptoms  and  signs  met  in  cases 
of  pernicious  malaria.  Le  Dantec22G  records  the  following 
case,  occurring  in  the  person  of  his  friend,  Dr.  Grosset,  who, 
after  several  paroxysms  of  intermittent,  was  taken  in  the 
course  of  an  attack  of  fever  with  dyspnea.  Percussion  showed 
incomplete  dulness  throughout  the  entire  extent  of  the  chest. 
Auscultation  revealed  crepitant  rales.  The  face  and  finger 
nails  were  cyanosed,  the  intelligence  was  unimpaired,  but  the 
peripheral  sensibility  had  almost  disappeared.  The  chest  was 
covered  with  cupping-glasses,  and  several  hypodermic  injec- 
tions of  quinine  were  given.  This  alarming  condition  lasted 
almost  twenty-four  hours,  when,  at  the  moment  a  fatal  issue 
was  expected,  the  sensibility  returned  and  every  trace  of  pul- 
monary congestion  disappeared  as  if  by  magic.  Cases  pre- 
senting profuse  hemorrhages  from  the  lungs  and  nose  have 
been  recorded  but  rarely. 

The  pathogenesis  of  this  condition  is  not  known,  as  there 
have  been  insufficient  post  mortems.  From  analogy  with  find- 
ings in  other  forms  of  pernicious  malaria  these  cases  must  be 
attributed  to  accumulations  of  parasites  in  the  pulmonary  capil- 
laries. Griesinger290  early  compared  the  filling  up  of  the  lung 
that  takes  place  in  these  cases  to  the  enlargement  of  the 
spleen. 

Abdominal  Forms. — The  representative  type  of  abdominal 
pernicious  malaria  is  the  algid.  The  reasons  for  classing  this 
type  as  an  abdominal  form  have  been  briefly  stated  when  con- 
sidering the  pathogenesis  of  the  different  varieties.  The  pic- 
ture presented  is  that  of  abdominal  shock,  it  is  peritonism 
minus  the  peritonitis. 

Torti  believed  that  the  algid  attack  was  merely  the  intensi- 
fication of  the  cold  stage  of  a  malarial  paroxysm.  But  there 
are  essential  differences.  First,  the  algid  attack  almost  always 
occurs  during  the  febrile  period  and  does  not  correspond  in 
time  to  the  first  stage.  Secondly,  in  the  cold  stage  of  the  ordi- 
nary paroxysm  the  patient  experiences  a  sensation  of  chilliness ; 


CLINICAL    HISTORY  213 

in  the  algid  attack  the  patient  feels  that  he  is  "burning  up," 
while  the  skin  feels  cool  to  the  observer.  The  algid  symptoms 
may  appear  insidiously,  but  much  more  frequently  supervene 
after  the  course  of  one  or  more  simple  paroxysms.  Usually 
the  first  symptoms  that  attract  the  attention  to  the  condition 
of  the  patient  are  the  bad  pulse  and  cold  surface.  Soon  the 
Hippocratic  facies  is  assumed.  The  eyes  are  deeply  sunken 
and  surrounded  by  dark  circles,  the  nose  appears  sharp,  the 
alse  nasi  dilate  with  respiration,  the  tip  of  the  nose  and  the 
ears  are  icy  cold.  The  temples  and  cheeks  are  hollowed,  the 
cheek  bones  project,  the  pupils  are  dilated,  the  conjunctivae 
bluish  white,  the  eyes  have  a  peculiar  anxious  expression,  and 
the  breath  is  cool.  The  skin  is  pale,  having  the  appearance  of 
absolute  bloodlessness  rather  than  that  of  cyanosis.  The  sur- 
face of  the  body  is  bathed  with  a  clammy  sweat,  is  cold,  and 
gives  the  sensation  to  the  hand  of  handling  a  catfish.  The 
fingers  and  toes  often  have  the  shrunken  appearance  of  the 
washerwoman's  hand.  The  prostration  is  extreme  and  the 
voice  is  weak,  low,  and  cracked.  The  patient  complains  of 
burning  heat  within  and  begs  piteously  for  cold  drinks,  which 
are,  as  a  rule,  immediately  rejected  by  the  stomach.  The 
intelligence  remains  clear  and  occasionally  "the  patient,  over- 
come by  sad  apprehensions,  considers  himself  lost,  bewails  his 
situation,  but  is  not  delirious,"  though  usually  he  is  indifferent 
to  his  peril.  The  temperature  may  be  subnormal  or  slightly 
elevated,  seldom  reaching  104°  F.  The  pulse  is  rapid,  fili- 
form, of  low  tension,  and  often  intermittent.  Later  it  usu- 
ally becomes  imperceptible  at  the  radial.  The  heart  sounds  are 
extremely  feeble.  The  respiration  is  very  rapid,  superficial, 
and  frequently  interrupted  with  deep  sighs.  The  tongue  is 
tremulous,  cold,  and  usually  moist  and  smooth.  Vomiting  is 
a  common  symptom.  The  bowels  are  sometimes  constipated, 
but  often  loose.  The  abdomen  may  be  slightly  tympanitic,  or 
scaphoid  and  tender,  especially  in  the  upper  half.  The  urine 
is  scanty,  highly  colored,  and  of  high  specific  gravity.  The 
duration  of  the  attack  is  short,  rarely  longer  than  twelve 
hours  after  the  onset  of  algidity.  In  fatal  cases  the  symptoms 
progress  rapidly  and  the  patient  dies  as  if  in  peaceful  sleep. 


214  THE   STUDY   OF  MALARIA 

In  favorable  cases  the  character  of  the  circulation  and  respira- 
tion improves,  the  body  warmth  is  gradually  restored,  the 
patient  ceases  to  complain,  and  convalescence  is  impeded  only 
by  the  extreme  weakness. 

When,  in  addition  to  the  symptoms  of  algidity  already  de- 
tailed, there  exist  symptoms  simulating  true  cholera,  there  is 
the  variety  of  algid  malaria  usually  spoken  of  as  choleraic 
pernicious.  The  onset  is  with  profuse  diarrhea  and  vomiting. 
The  stools  are  thin  and  watery  and  often  rice-water-like. 
There  may  likewise  be  shown  the  muscular  cramps  of  the 
lower  limbs  frequent  in  cholera.  The  temperature  is  usually 
elevated  and  pains  in  the  abdomen  and  precordia  and  singultus 
may  be  experienced.  The  urine  is  usually  scanty  and  may  be- 
come suppressed. 

The  condition  of  algor  with  which  drenching  diaphoresis 
occurs  constitutes  the  so-called  sudoral  or  diaphoretic  form 
of  pernicious  fever.  These  sweats,  which  are  so  profuse  that 
not  only  the  clothing  of  the  patient,  but  also  the  bedclothes  are 
saturated,  usually  supervene  toward  the  close  of  a  paroxysm. 
The  celebrated  Torti,  who  was  himself  the  victim  of  such  an 
attack,  says  that  he  was  just  congratulating  himself  upon 
escaping  the  fever  when  the  abundant  sweats  occurred  to  con- 
vince him  that  his  condition  was  critical. 

In  the  course  of  an  algid  access  syncope  occasionally  occurs 
when  any  exertion,  even  the  slightest,  is  attempted  or  when 
the  patient's  head  is  lifted  from  the  pillow.  This  dangerous 
symptom  usually  comes  quite  unexpectedly,  and  if  the  patient 
survives  the  first  onset  a  subsequent  one  may  rapidly  prove 
fatal. 

The  gastralgic  or  cardialgic  type  is  characterized  by  excru- 
ciating pain  in  the  abdomen,  especially  the  epigastric  region, 
or  in  the  precordia.  The  pain  is  often  so  intense  that  the 
patient  doubles  up  and  rolls  in  agony  upon  the  bed.  The 
abdomen  is  tender  and  vomiting  is  a  common  symptom.  There 
may  be  hematemesis,  sometimes  profuse.  Diarrhea  and  singul- 
tus are  occasional  symptoms. 

While  the  existence  of  dysenteric  pernicious  malaria  has 
been  denied  by  Colin291  and  more  recently  by  Kanellis  and  Car- 


CLINICAL    HISTORY  215 

damatis,292  the  frequent  occurrence  of  severe  dysenteric  symp- 
toms, due  solely  to  malarial  infection,  has  been  definitely  dem- 
onstrated by  Craig.293  The  attack  may  follow  other  forms  of 
abdominal  pernicious  or  may  come  on  suddenly.  There  are 
frequent  actions  of  bloody  mucus,  violent  tenesmus,  colicky 
pains  in  the  abdomen,  elevation  of  temperature,  and  sometimes 
emaciation.  Algid  symptoms  are  not  common.  Occasionally 
abundant  hemorrhages  from  the  bowels  occur.  They  may 
prove  rapidly  fatal,  especially  if  the  patient  is  already  mark- 
edly anemic. 

Icterus  and  bilious  vomiting  are  not  rare  in  malaraia.  As 
a  rule,  these  are  not  grave  symptoms,  but  there  are  cases  in 
which  their  persistence  and  intensity  form  a  complex  of  symp- 
toms described  as  bilious  pernicious  malaria.  The  fever  is 
usually  high,  nausea  constant,  icterus  marked,  and  vomiting 
of  bile  distressing.  Bile  is  present  in  the  urine,  often  in  quan- 
tities, and  sometimes  albumin.  Epistaxis  and  hematemesis 
have  been  noted.  The  epigastrium  is  often  painful  and  singul- 
tus may  add  to  the  discomfort  of  the  patient.  Toward  the  end 
of  the  severe  cases  there  are  apathy  and  carphology,  and  the 
scene  usually  closes  with  delirium  and  coma. 

Waton290  observed  a  case  with  symptoms  resembling  those 
of  peritonitis.  Laveran1  refers  to  several  similar  cases.  Gil- 
lot294  treated  3  cases  in  which  the  clinic  picture  was  identical 
with  that  of  acute  peritonitis.  One  case  which  he  diagnosed  as 
perforation  due  to  typhoid  ulceration  was  operated  upon.  The 
operation  proved  a  mistaken  diagnosis.  The  blood  was  exam- 
ined, malarial  parasites  found,  and  the  patient  recovered 
promptly  after  the  subcutaneous  injection  of  il/>  grams  of 
quinine. 

Wolf,295  Chamberlain,296  and  Craig297  report  cases  presenting 
symptoms  which  would  lead  to  a  diagnosis  of  appendicitis. 
Ford180  records  5  such  cases,  one  of  which  was  operated  upon 
and  the  appendix  found  to  be  healthy. 

Ross  and  Daniels298  performed  an  autopsy  on  a  man  who 
was  not  supposed  to  have  died  of  malaria,  and  found  a  hemor- 
rhagic pancreatitis  with  extensive  massing  of  parasites  in  the 
pancreas.     Parasites  were  also  very  numerous  in  the  capil- 


2l6  THE    STUDY   OF   MALARIA 

laries  of  the  stomach  and  intestines,  and  these  organs  showed 
extensive  necrosis. 

The  urine  is  usually  highly  colored.  The  amount  varies 
inversely  with  the  quantity  of  sweat,  bowel  movement,  and 
vomited  matter,  the  specific  gravity  varies  inversely  with  the 
amount.  Early  in  the  attack  albumin  may  be  absent,  though 
later  it  is  often  present  in  large  quantities,  together  with 
numerous  tube  casts. 

The  blood  in  various  forms  of  pernicious  malaria  shows, 
besides  parasitic  findings  previously  mentioned,  a  pronounced 
reduction  of  red  cells,  averaging  a  half  to  one  million  per 
paroxysm.  Polychromatophilia  of  red  cells  may  be  observed. 
Contrary  to  the  case  of  simple  malaria,  there  is  usually  a  pro- 
nounced leukocytosis.  There  may  be  as  many  as  35,000  per 
cm.  Thayer98  observed  a  case  of  the  algid  type  in  which  there 
were  50,000  in  number.  The  differential  formula  usual  in 
malaria,  the  relative  increase  of  large  mononuclear  elements, 
is  maintained.  According  to  Billet,151  the  average  of  these 
cells  is  10-15  per  cent. ;  in  9  of  his  40  cases  it  varied  from  20-25 
per  cent,  and  in  1  case  they  existed  in  the  proportion  of  30  per 
cent.     Great  numbers  of  these  cells  were  pigmented. 

HEMOGLOBINURIC  FEVER 

Hemoglobinuric  fever  is  known  by  many  names,  some  of 
which  are  mere  localisms.  Among  the  more  general  synonyms 
are:  malarial  hematuria,  hemoglobinuric  fever,  swamp  fever, 
blackwater  fever,  bilious  hematuric  fever,  melanuric  fever,  etc. 

After  a  severe  chill  the  temperature  rises  rapidly  and  a 
copious  discharge  of  red,  almost  black,  urine  is  voided.  The 
patient  complains  of  headache  and  pain  in  the  loins  and  epigas- 
trium, and  is  afflicted  with  nausea  and  violent  bilious  vomiting. 
Thirst  is  torturing  and  insatiable  because  of  the  gastric  dis- 
turbance. There  may  be  more  or  less  tympanites.  The  liver 
and  spleen,  especially  the  latter,  may  be  enlarged  and  tender. 
In  a  few  hours  icterus  begins  and  the  patient  soon  becomes  as 
yellow  as  a  pumpkin.  He  is  very  restless  and  has  an  anxious 
expression.     If  the  attack  is  mild  the  duration  may  not  be 


CLINICAL    HISTORY 


217 


longer  than  that  of  an  ordinary  malarial  paroxysm ,  the  vomit- 
ing ceases,  pain  disappears,  the  urine  gradually  clears,  the 
temperature  falls  to  normal  or  a  little  below,  and  the  patient  is 
comparatively  comfortable  excepting  a  degree  of  weakness. 
The  jaundice  usually  lasts  a  day  or  two  longer.  In  rare  cases 
the  duration  of  the  attack  is  extremely  short,  the  urine  voided 
at  a  single  act  only  being  hemoglobinuria 

In  severer  cases  the  temperature  may  drop,  but  not  to  nor- 
mal; vomiting  is  incessant,  the  urine  continues  darkly  colored 
and  becomes  scantier.  Rigors  may  occur  at  irregular  intervals, 
followed  by  a  rise  of  temperature,  deepening  of  the  color  of 


< 

U 

0, 

S 
u 

H 

m.  m. 

300 

290 
280 
270 
260 
230 
240 
230 
220 
210 
200 
190 
180 
170 
160 

DAY  OF 
DISEASE 

DAY  OP 
MONTH 

HOUR. 

: 

:ent. 
41»— 

40°— 

39°— 

38»- 

3*7°- 
36°- 

FAH. 

106° 
10SO 
1040 
1030 
1020 
101° 
100° 

990 

980 
970 
96° 

■ 

'■ 

: 

•J 

f 

I 

\L 

: 

** 

eh 

--** 

r- 

Fig.  59. — Hemoglobinuric  fever  ;  mild. 


\< 

UJ 
Cu 

N 

r 

300 
290 
280 
270 
260 
2S0 
240 
230 
220 
210 
200 
190 
180 
170 
160 

DAY  OF 
DISEASE 

DAY  OF 

MONTH 

HOUR. 

CENT. 
410— 

40°— 

39°_ 

330- 

370- 

36»- 

3S»- 

RAH. 
106° 

10S° 

104O 

103P 

102° 

101° 

100" 

99° 

98» 

970 

%o 

1 

> 

; 

I 

f 

V 

i 

1 

ll 

\ 

\ 

! 

1: 

I- 

- 

Fig.  60. — Hemoglobinuric  fever  ;  death. 


the  urine,  and  marked  prostration.  The  urine  may  become 
suppressed  and  death  takes  place  in  a  few  days.  Or  the  patient 
may  die  suddenly  while  being  raised  to  use  the  vessel  or  to 
take  medicine  or  nourishment. 

The  attack  may  be  preceded  by  one  or  more  malarial  parox- 
ysms or  may  come  on  suddenly.  There  may  be  prodromata 
consisting  of  general  malaise,  aching  in  the  loins  and  head, 
nausea,  and  a  slight  rise  of  temperature,  though  this  latter  may 
be  imperceptible  to  the  patient.     In  more  than  nine-tenths  of 


2l8  THE   STUDY   OF  MALARIA 

the  cases  the  onset  is  with  a  rigor,  usually  intense  and  pro- 
tracted. Sometimes,  as  in  ordinary  malaria,  the  first  stage  is 
obscure  or  wanting,  and  the  attack  begins  with  fever  and 
vomiting.  Occasionally  the  passage  of  black  water  precedes 
the  other  symptoms,  as  in  one  of  my  cases,  where  the  patient 
had  had  a  mild  rigor  the  day  before,  but  felt  well  enough  to 
ride  out  on  horseback  in  search  of  his  cow.  While  five  miles 
from  home  he  was  dumbfounded  at  passing  an  abundance  of 
almost  black  urine.  He  immediately  set  out  to  consult  me,  and 
had  ridden  six  miles  when  he  was  prevailed  upon  to  return 
home.  Death  from  exhaustion  occurred  on  the  fourth  day. 
Rarely  the  onset  is  characterized  by  violent  pain  in  the  abdo- 
men. The  intensity  of  the  onset  is  no  guide  to  the  severity 
of  the  attack. 

There  are  four  symptoms  which  are  present  in  nearly  all 
cases.  These  are :  fever,  hemoglobinuria,  icterus,  and  vomit- 
ing. 

There  is  nothing  characteristic  in  the  temperature.  Its  usual 
range  is  from  ioi°  to  105°  F.  Hyperpyrexia  is  unusual, 
though  very  high  temperatures  have  been  recorded.  Thus 
Marsden269  noted  a  case  in  which  the  temperature  reached 
1 09°  F.  Cases  in  which  the  temperature  is  normal  or  sub- 
normal throughout  are  not  unknown ;  for  example,  2  reported 
by  Baldwin  Seal.258  Neither  of  these  patients  had  taken  any 
quinine.  As  a  rule,  in  mild  cases  the  temperature  reaches  the 
fastigium  shortly  after  onset,  from  which  point  it  drops  pro- 
gressively to  or  a  little  below  normal.  In  other  cases  it  is 
intermittent,  remittent,  or  irregular,  and  may  resemble  the 
curve  of  septic  fever.  When  rigors  occur  during  the  course 
they  are  accompanied  by  a  rise  of  temperature.  Periodicity  is 
not  a  conspicuous  feature  nor  is  the  characteristic  curve  of 
Marchiafava  and  Bignami  seen.  The  average  duration  of  the 
fever  is  from  a  few  hours  to  several  days.  It  usually  outlasts 
the  hemoglobinuria,  but  not  in  all  cases.  The  height  of  the 
temperature  in  hemoglobinuria  fever  is  possessed  of  little  or 
no  prognostic  import. 

A  rare  occurrence  is  the  obstinate  tenacity  or  subsequent  rise 
of  the  fever  after  hemoglobinuria  has  subsided.     The  duration 


Fig.  61. — A  convalescent  from  blackwater  fever.     The  line  indicates  the  border 

of  the  spleen. 


CLINICAL   HISTORY  219 

of  this  posthemoglobinuric  fever  is  variable.  In  2  of  Brem's215 
cases  it  was  fourteen  and  eighteen  days;  in  3  of  my  cases 
twelve,  nineteen,  and  twenty-eight  days;  in  1  of  Bank's210 
over  five  weeks ;  in  1  of  Howard's  216  six  weeks.  Outbursts  of 
hemoglobinuria  occasionally  occur  during  this  fever.  In  most 
of  the  cases  the  temperature  rose  higher  than  during  the  hemo- 
globinuric  period.  It  is  entirely  uninfluenced  by  quinine  and 
is  probably  related  to  the  spodogenous  fever  of  Marchiafava 
and  Bignami,22  or  postmalarial  secondary  fever.  The  mortal- 
ity of  these  cases  seems  to  be  low. 

Schellong92  observed  a  peculiar  case  which  showed  a  post- 
mortem elevation  of  temperature.  The  fever  began  to  rise  a 
few  minutes  after  death,  and  more  than  an  hour  later,  when 
last  recorded,  the  temperature  was  106.2°  F.  The  ther- 
mometer registered  higher  in  the  right  axilla  than  in  the  left 
throughout  the  observation. 

Probably  in  no  other  condition  do  we  see  such  rapid  and  pro- 
found transition  in  the  state  of  the  urine.  A  few  hours  before 
the  onset  the  urine  is  normal,  afterward  it  may  show  all  the 
characteristics  detailed  below.  In  favorable  cases  the  return 
to  normal  is  remarkable. 

The  quantity  varies  within  very  wide  limits.  In  mild  attacks 
it  may  not  vary  from  that  of  health.  Often  at  first  there  is 
an  increase,  a  decided  decrease  at  the  height  of  the  attack, 
gradually  increasing  to  normal  or  above  with  improvement. 
In  suppression  cases  there  is  usually  a  diminution  from  the 
first,  resulting  in  total  anuria  or  the  passage  of  only  a  few 
ounces  daily.  Anuria  is  due  to  the  plugging  of  the  renal 
tubules  and  to  diminution  of  blood  pressure.  Pain  resembling 
that  of  renal  colic  may  be  experienced  with  anuria.  The  tem- 
perature may  remain  normal  throughout  suppression  of  several 
days'  duration.  It  occasionally  happens  that  urinary  secretion 
is  reestablished  after  anuria  has  persisted,  even  as  long  as  five 
days ;  in  such  cases,  however,  most  die  of  complications  during 
convalescence.  The  outlook  is  very  grave  when  suppression 
lasts  longer  than  twenty- four  hours.  Death  usually  takes  place 
after  three  or  four  days,  though  Plehn5  reports  a  fatal  case 
where  life  was  prolonged  twelve  days  after  the  onset  of  sup- 


220  THE   STUDY   OF   MALARIA 

pression,  and  Kudicke51  observed  2  fatal  cases  in  which  anuria 
persisted  thirteen  days. 

The  color,  often  described  as  "port  wine,"  varies  from  a 
light  claret  to  that  of  black  coffee.  The  latter  color  obtains 
when  the  urine  of  a  severe  attack  is  examined  in  a  thick  layer 
by  reflected  light.  In  a  test-tube  by  transmitted  light  it  ap- 
pears of  a  lighter  color.  The  froth  varies  from  yellow  to  red- 
dish ;  a  greenish  color  is  said  to  be  due  to  the  presence  of  bile. 
The  coloring  matter  is  more  often  in  the  form  of  methema- 
globin,  though  oxyhemaglobin  is  found.  It  is  probably  not 
present  in  a  true  solution,  since  it  is  more  abundant  in  the 
sediment  of  a  centrifugalized  urine  than  in  the  supernatant 
fluid,  and  disappears  from  the  latter  first  with  improvement. 
The  hemoglobinuria  may  be  intermittent  or  continuous.  Ste- 
phens and  Christophers118  observed  that  blackwater  urine  made 
alkaline  with  potash  and  then  boiled  produced  a  purple  color, 
giving  the  bands  of  hemochromogen,  showing  that  the  urine 
itself  contained  reducing  bodies.  A.  Plehn  mentions  that  on 
boiling  the  urine  and  allowing  it  to  stand  for  some  time  a 
bright  purple  color  appears.  On  standing  an  abundant  dirty 
brownish  sediment  is  deposited,  the  amount  varying  with  the 
concentration  of  the  fluid.  The  urine  stains  linen  a  dirty  red. 
The  reaction  is  generally  slightly  acid,  but  may  be  neutral  or 
alkaline.  The  specific  gravity  varies  inversely  with  the  quan- 
tity. Albumin  is  always  present.  It  is  commonly  in  excess 
of  the  hemoglobin  and  persists  for  a  longer  period,  though  the 
curves  run  more  or  less  parallel.  Serum  albumin,  albumose, 
globulin,  and  nucleo-albumin  are  found.  Plehn5  gives  the 
limits  of  quantity  as  ^2-2  grams  per  liter,  estimated  according 
to  Esbach's  method.  The  writer  has  very  frequently  observed 
twice  as  much  as  his  maximum  limit,  and  in  1  of  his  cases  the 
amount  was  14  grams  with  the  Esbach  instrument.  Some 
urines  on  being  boiled  become  almost  completely  solidified. 
Bile  is,  as  a  rule,  absent;  it  is  never  present  in  proportion  to 
the  polycholia.  It  was  not  found  by  the  Plehns5  or  by  Daniels57 
in  any  of  their  cases.  Urobilin  is  common.  Stephens  and 
Christophers118  assert  that  it  occasionally  appears  before  the 
attack,  but  more  constantly  after  the  oxyhemoglobin  has  dis- 


Mo.        /mi            . ..Admitted. /S^jt-j.,?.., ../.£/?.£ _           __ 

*fi      ay..,a              t«                      «.i                   u.                     *  3                     jl  *                    J  J            ^tf^OhiAtx ti^ ^ — iff                       a«                     1»               «...    .                      j                  j 

108  HEp     J_;                  4 -, J ■■ -i 

vn[l\\  |j]                                                  fj---          -               j                                                    |                                     ~H      1  1      1  1 

los  -tZj ^    _•  •                      5 ; .|! Z|Z_ SJ i . —        _, 

I05  iilzjEjzzzizjzzzzzizzzzjzzzzzjzz  izzjzzzzzlizzzz-izzzzziizzzzz:!  zzzzlzzzzz r 

1MzHi  il    z:  z  zz          z  n      z    i      :          zzzzt  z  i      -_          -_z      — : z --J: 

::: WfWm  If  tU-Mil  liri  Biill    111  1 IM 

99 4 "3 " 1 3 "j ^4 

98   ">^ 

q7  »_sS 1 -»__!.- £_^.^c_^__i  —  I A — 1; i — :: i- ' 

f.Cfe  N; Lffillilffl  U  hfeH*    H                            I    i      -  J                                                '  T 
*»  "5    }|iBi^  s-i  ^                                            :_*    i    t  i    ±    i    t    t ^ J--T-I- 

£- fc  i- - 

&*&=======— —^:-=*='>t-t-«-a  =  ^t=.!,.a=._t=Jt3.9: — —  *_«-=,  _a. — «- -a  — =-=*    -    -4*„ *_ 

Srools           of                       1                        c                        c                    .    *                         t                        .to                      0 

Urlm                              i'°!                    '■'""                  •*'■  1  '                   ■r!"                '■•*!  '                     z.i°c            -":"    aS"'             *'?«                i.cfc                     t  u 

Zl\  »|         ^             ^             i             7              t              ^           «j  ,„          Y              ,«.            ,i             ^     j        „-           ,< 

Posthemoglobinuric  fever  (after  Brem). 


CLINICAL   HISTORY  221 

appeared,  or  together  with  it.  Marchoux299  maintains  that 
quinine  cannot  be  detected  in  the  urine  during  the  hemoglobin- 
uric  period,  but  appears  later.  But  the  observations  of  Giemsa 
and  Schaumann300  do  not  sustain  this  opinion.  They  found  the 
amount  of  quinine  excreted  with  the  urine  during  the  attack 
is  somewhat  larger  than  otherwise,  and  that  the  excretion  is 
extended  over  a  longer  period  of  time  in  a  regularly  increas- 
ing and  decreasing  curve  which  is  uninfluenced  by  the  hemo- 
globin content  of  the  urine.  This  increased  excretion  of 
quinine  in  the  urine  in  hemoglobinuric  fever  would  lead  to  the 
inference  that  the  organism  is  not  capable,  as  it  usually  is,  of 
protecting  itself  from  the  poisonous  alkaloid  by  splitting  the 
molecule.  Marchoux299  claims  that  hemoglobinuric  fever 
urine  has  no  hemolytic  action  on  the  red  blood-cells  of  normal 
persons. 

On  microscopic  examination  the  field  appears  littered  with 
a  brownish  amorphous  detritus,  the  products  of  broken-down 
red  blood  corpuscles.  Whole  red  blood-cells  are  not  generally 
found  and  rarely  in  considerable  numbers.  Casts  are  abun- 
dant, especially  the  granular;  also  hyaline  and  epithelial. 
These  casts  are  sometimes  almost  covered  with  the  granular 
pigment.  Renal  and  vesical  epithelium  are  common,  and 
mucus  and  crystals  of  hematoidin  may  be  found.  Leucin  and 
tyrosin  are  rare.  Williams,301  Mackey302  and  Brem215  have 
described  different  peculiar  bodies  found  in  the  urine.  The 
nature  and  significance  of  these  bodies  are  unknown. 

There  are  often  present  vesical  tenesmus  and  pain  over  the 
bladder.  Retention  of  urine,  burning  in  the  urethra,  and  ten- 
derness over  the  kidneys  are  not  uncommon  symptoms.  The 
urine  may  be  voided  drop  by  drop. 

After  a  few  hours  jaundice  begins  to  appear  and,  except  in 
the  mildest  cases,  develops  rapidly  until  the  skin  and  sclera 
are  of  a  pronounced  saffron  yellow-.  It  usually  outlasts  the 
fever  a  few  days.  Itching  of  the  skin  is  not  common.  Herpes 
is  relatively  infrequent  and  petechias  are  rare.  The  occurrence 
of  the  latter  is  said  to  imply  a  grave  prognosis.  Edema  or 
anasarca  may  be  encountered,  especially  in  cases  where  there 
is  unusual  involvement  of  the  kidneys.     Sweats  may  occur  with 


222  THE   STUDY   OF   MALARIA 

the  decline  of  the  fever  or  with  collapse.  The  skin  is  often 
dry.  Sometimes  the  perspiration  is  charged  with  bile  pigment. 
Banks210  mentions  a  peculiar  odor  emanating  from  blackwater 
fever  patients.  He  claims  that  it  enables  one,  together  with 
the  expression,  to  make  a  diagnosis  before  the  urine  is  exam- 
ined. So  far  as  the  writer  knows,  he  has  not  been  corrobo- 
rated, though  in  suppression  cases  a  uremic  odor  may  be  per- 
ceptible. 

Vomiting  is  usually  one  of  the  earliest  symptoms  and  fre- 
quently the  most  distressing.  After  the  stomach  contents  are 
voided  the  vomit  consists  of  a  yellowish  or  green  bile.  Occa- 
sionally it  is  a  grass-green  or  peculiar  bluish-green,  or  it  may 
be  very  dark,  almost  black,  somewhat  resembling  the  black 
vomit  of  yellow  fever.  The  vomiting  is  independent  of  the 
taking  of  food,  and  is  probably  more  or  less  of  central  origin. 
In  very  mild  cases  vomiting  may  be  very  insignificant  or 
absent.  Nausea  is  usually  in  proportion  to  the  vomiting.  The 
bowels  may  be  constipated  or  there  may  be  a  bilious  diarrhea. 
Occasionally  the  dejections  are  thin  and  watery,  of  a  reddish- 
brown  color,  and  may  closely  resemble  the  urine. 

This  is  thought  to  be  due  to  the  extravasation  of  hemoglo- 
binuric  serum  into  the  intestine,  and  is  usually  seen  in  severe 
cases  only.  Dysenteric  symptoms  are  infrequent.  Hemor- 
rhage from  stomach  or  bowel  is  rare.  Meteorism  is  not  an 
infrequent  symptom.  There  may  be  severe  colicy  pains  in  the 
abdomen.  Pain  is  usually  present  in  the  epigastric  region  or 
over  the  liver  and  spleen.  These  are  usually  tender,  the  spleen 
often  greatly  enlarged,  the  liver  less  so.  The  appetite  in  all 
but  mild  cases  is  completely  lost.  Thirst  is  intense  and  cannot 
be  alleviated  for  the  vomiting.  The  tongue  is  anemic  and 
heavily  coated.  Sordes  of  the  teeth  and  lips  are  often  seen  in 
extreme  cases.  The  saliva  may  stain  the  linen  a  brownish- 
yellow.  The  pulse  is  rapid,  out  of  proportion  to  the  tempera- 
ture, at  first  full  and  bounding,  later  small  and  compressible. 
A  hemic  murmur,  systolic  in  time,  is  sometimes  heard  over  the 
precordia,  not  transmitted.  Respiration  is  accelerated.  There 
is  often  sense  of  oppression  in  the  chest.  Dyspnea  may  be  a 
prominent  symptom,  due  to  anemia  or  to  edema  of  the  lungs. 


CLINICAL   HISTORY  223 

There  may  be,  especially  after  some  days  of  severe  illness, 
slight  dulness  and  diminished  respiratory  murmur  over  the 
dependent  portions  of  the  lung,  accompanied  by  slight  cough, 
resulting  from  hypostatic  congestion.  Cheyne-Stokes  respira- 
tion may  appear  toward  the  end.  Hiccough  is  present  in  a 
large  per  cent,  of  fatal  cases,  and  if  obstinate  is  always  to  be 
regarded  unfavorably.    Epistaxis  is  occasionally  seen. 

Anemia  increases  with  intense  rapidity,  half  the  red  cells 
sometimes  being  destroyed  in  twenty-four  hours.    The  number 
usually  falls  to  one  to  two  million  during  the  attack.     Except 
for  the  absolute  diminution  of  the  fluid  portion  of  the  blood 
as  a  consequence  of  purging  and  vomiting,  the  number  of  red 
cells  per  c.mm.  would  appear  much  smaller  than  it  does.     It 
is  occasionally  difficult  to  obtain  a  drop  for  examination  by 
the  usual  method.     It  appears  relatively  thinner  than  normal 
and  the  cover-glass  may  adhere  to  the  oil-immersion  objective 
rather  than  to  the  slide.    On  coagulation  the  serum  may  appear 
yellow    (cholemia)    or    reddish    (hemoglobinemia),    though 
neither    is    constant.      Macrocytes,    microcytes,    poikilocytes, 
shadows,  polychromatophiles,  and  basophiles  are  found,  but  not 
always,  as  pathologic  cells  may  succumb  early.     One  is  often 
surprised  to  see,  notwithstanding  the  extreme  hemolysis,  the 
erythrocytes  presenting  so  few  changes.     Nucleated  reds  may 
be  found,  especially  during  convalescence.     The  color  index 
shows  nothing  characteristic;  it  may  be  normal  or  above,  at 
first  falling  gradually  until  convalescence  is  established.     The 
hemoglobin  per  cent,  usually  runs  parallel  with  the  red  cell 
count.    It  is  generally  reduced  to  25  to  50  per  cent.,  sometimes 
lower,  as  in  a  case  of  Hoffmann,49  in  which  the  patient  recov- 
ered notwithstanding  a  fall  to  12  per  cent.    It  is  often  asserted 
that  during  pyrexia  there  is  a  leukocytosis,  and  the  polymor- 
phonuclears are  increased  often  to  90  per  cent.     With  falling 
temperature  there  is  a  pronounced  large  mononuclear  increase 
with  leukopenia.     However,  the  average  of  a  number  of  differ- 
ential counts  made  at  irregular  intervals  during  the  attack 
shows  a  marked  increase  in  the  large  mononuclears,  a  decided 
diminution  of  small  mononuclears,  and  a  slight  increase  of 
polymorphonuclears.       Pigmented    leukocytes    are    common. 


224  THE   STUDY   OF   MALARIA 

Christophers  and  Bentley303  have  made  interesting  observations 
on  the  phagocytosis  of  red  blood  corpuscles  in  the  spleen  of  a 
case  of  blackwater  fever.  In  a  differential  count  of  2,200 
spleen  cells  1.7  per  cent,  were  large  macrophages  containing 
red  cells  and  1.3  per  cent,  were  small  mononuclear  cells  con- 
taining red  blood-cells.  In  both  kinds  of  cells  were  seen  blood 
corpuscles  showing  no  evident  alterations,  corpuscles  more  or 
less  decolorized,  and  clear  vacuoles  about  the  size  of  red  blood- 
cells.  The  closest  scrutiny  of  the  engulfed  cells  failed  to  reveal 
the  presence  of  parasites  or  other  evidence  of  parasitic  invasion. 
This  extensive  phagocytosis  of  apparently  normal  cells  is  of 
interest  from  the  standpoint  of  pathogenesis.  The  platelets 
are  numerous  and  of  large  size.  The  alkalinity  of  the  blood  is 
often  diminished.  In  spite  of  the  destruction  of  red  cells  the 
specific  gravity  remains  relatively  high.  This  is  no  doubt  due 
to  the  quantity  of  material  in  solution  in  the  serum.  During 
convalescence  the  specific  gravity  falls.  Stephens  and  Christo- 
phers57 give  the  following  as  the  result  of  their  observation  on 
tonicity :  "In  blackwater  there  is  occasionally  a  remarkably  low 
tonicity;  in  other  cases  it  has  the  normal  value  or  somewhat 
raised  value,  as  in  malaria.  The  low  or  normal  value  in  black- 
water  may  be  due,  as  we  have  previously  suggested,  to  the  fact 
that  the  weak  corpuscles — those  of  high  tonicity — are  de- 
stroyed, or  it  may  be  due  to  the  fact  that  the  tonicity  of  the 
corpuscles  as  a  whole  is  changed  after  the  liberation  of  hemo- 
globin." The  presence  of  malarial  parasites  has  been  dealt 
with. 

Blackwater  fever  is  not  a  very  painful  affection,  but  the 
vomiting  and  thirst  make  the  patient  intensely  wretched.  Be- 
sides the  abdominal  pains  there  are  headache  and  aching  of  the 
back  and  limbs.  He  is  usually  terrified  at  the  appearance  of 
the  urine.  His  expression  is  one  of  anxiety  and  apprehension, 
and  a  fear  of  death  often  seizes  him.  He  is  restless  and  irri- 
table. In  children  especially  there  is  frequent  tossing  of  the 
head  from  side  to  side.  Later  there  is  prostration,  intense 
languor,  perhaps  somnolence.  Formication  and  numbness  in 
the  fingers  and  toes  are  occasional  complaints.  Delirium  when 
present  is  usually  quiet.     When  suppression  ensues  the  symp- 


CLINICAL    HISTORY  225 

toms  may  be  typic  of  those  in  uremia,  but  this  is  not  con- 
stant ;  delirium  may  be  of  the  low,  muttering  variety ;  convul- 
sions are  often  missing,  and  the  mind  may  be  clear  until 
shortly  before  death,  when  coma  supervenes.  There  may  be 
involuntary  discharge  of  urine  and  feces. 

The  causes  of  death  are  three :  Suppression  of  urine,  exhaus- 
tion, and  cardiac  paralysis.  Suppression  is  the  commonest 
cause.  This  sometimes  takes  place  when  the  urine  is  clearing 
or  is  already  clear.  Uremic  symptoms  do  not  result  from  sup- 
pression in  blackwater  fever  as  frequently  as  in  other  condi- 
tions. This  is  probably  due  to  two  causes.  First,  elimination 
through  vomiting  and  purging  is  free ;  secondly,  metabolism  is 
diminished  as  the  result  of  deficient  oxygenation.  Exhaustion 
is  usually  the  result  of  the  tremendous  destruction  of  blood- 
cells,  together  with  inability  of  the  hematopoietic  organs  to 
meet  the  deficiency,  or  to  pyrexia.  Occasionally  hiccough  plays 
a  role  in  exhaustion.  The  patient  may  die  early  with  symptoms 
of  shock  or  may  linger  several  days  in  a  typhoid  state.  Cardiac 
paralysis  is  usually  due  to  thrombosis  of  the  heart.  Plehn5 
regards  this  as  a  common  cause  of  death.  Goltmann  and 
Krauss189  have  shown  that  in  some  cases  of  death  from  syncope 
there  exists  a  marked  cardiac  nerve  degeneration  and  empty 
cylinders. 

It  would  manifestly  be  of  great  practical  importance  if  the 
symptoms  of  an  impending  attack  of  hemoglobinuria  could 
be  recognized.  This  is  possible,  if  at  all,  only  in  a  very 
general  way.  Plehn2*  says  that  an  onset  is  to  be  feared 
when  the  patient  has  lived  some  six  months  in  a  blackwater 
fever  area  and  has  had  malaria  at  short  intervals,  when  this 
malaria  has  been  treated  improperly  with  insufficient  quinine 
dosage,  when  he  looks  downcast,  and  perhaps  shows  a  mild 
icterus  of  the  sclera  and  skin.  This  might,  however,  forebode 
a  relapse  of  ordinary  malaria.  Sometimes,  he  further  states, 
there  occurs  a  certain  depressed  condition,  a  characteristic 
mental  apathy  with  physical  restlessness,  phenomena  which  are 
hard  to  describe,  but  have  often  been  encountered  by  one- who 
has  seen  many  cases  develop.  Also  the  presence  of  albuminuria 
should  cause  suspicion,  as  this  tends  to  be  absent  in  simple 

15 


226  THE   STUDY   OF   MALARIA 

tropic  fever,  even  with  a  temperature  of  41°  C.  Koch90  des- 
ignates as  "blackwater  fever  candidates"  those  in  whom  a 
few  hours  after  taking  quinine  the  temperature  mounts  to 
38°  C.  or  more,  the  urine  becomes  decidedly  darker,  and  the 
next  morning  a  mild  icterus  is  evident.  Ziemann48  has  fre- 
quently observed  in  blackwater  fever  candidates  the  following 
blood  changes,  which,  however,  are  not  constant : 

1.  The  more  frequent  appearance  of  decided  basophile  and 
polychromatophile  degeneration  of  the  red  cells. 

2.  The  rapid  solution  of  the  red  cells  in  a  salt  solution,  in 
which  normal  cells  do  not  dissolve. 

3.  A  decided  diminution  of  the  coagulability  of  the  blood. 
This  writer  also  regards  urobilinuria  as  a  valuable  prognostic 

sign. 

Relapses  are  not  infrequent  and  several  may  occur,  often 
befalling  the  patient  when  he  is  thought  to  be  doing  well.  It 
may  be  difficult  to  distinguish  relapses  from  recurrences. 
Convalescence  may  very  properly  be  regarded  as  the  dividing 
line,  those  occurring  during  convalescence  being  considered  as 
relapses  and  those  later  as  recurrences.  Plehn208  believes  that 
recurrences  are  rare  unless  provoked  by  quinine.  Of  eighteen 
recurrences  recorded  by  Vedy213  one  occurred  after  less  than 
three  months,  fourteen  from  three  to  six  months,  two  from  six 
to  twelve  months,  and  one  longer.  It  is  remarkable  that  nine 
recurrences  happened  just  three  months  from  the  date  of  the 
last  attack.  The  writer's  experience  has  been  that  in  persons 
having  more  than  one  attack  the  attacks  are  more  often  sepa- 
rated by  intervals  of  a  year  or  more. 

Complications  and  Sequela. — These  are  singularly  few  in 
variety.  Nephritis  in  some  degree  is  an  almost  constant  com- 
plication, and  may  cause  death  from  suppression  during  the 
attack.  It  may  heal  in  a  remarkably  short  time.  As  a  sequela 
it  is  not  infrequent  and  may  persist  for  days  or  weeks,  causing 
slow  and  incomplete  convalescence  or  death.  The  changes  in 
the  kidney  may  be  attributed  to  the  irritating  effect  of  hemo- 
globinuric  urine  and  to  the  pyrexia. 

In  16  cases  the  writer  has  been  able  to  make  examinations 
of  urine  at  periods  varying  from  a  few  days  to  fourteen  years 


CLINICAL   HISTORY  227 

after  the  last  attack.    In  8  cases  the  examination  was  negative. 
The  others  may  be  noted  as  follows : 

F.  S.,  white,  male,  set.  17,  one  attack,  1899;  urinalysis,  Feb- 
ruary 27,  1907,  showed  a  trace  of  albumin,  no  casts,  no  symp- 
toms of  nephritis. 

A.  J.,  white,  male,  set.  18,  two  attacks,  last  one  October, 
1904;  urinalysis,  September  21,  1906,  showed  albumin  ^  gm. 
liter,  very  numerous  cylindroids  and  hyaline  casts,  moderate 
number  of  granular.     Anemia,  edema  of  lids  and  ankles. 

Mrs.  H.,  white,  female,  aet.  25,  one  attack  fourteen  years 
ago;  urinalysis,  September  25,  1906,  showed  the  presence  of 
albumin  and  a  few  granular  casts.    No  symptoms. 

M.  C,  white,  female,  aet.  10,  two  attacks,  last  one  Septem- 
ber 24,  1906;  urinalysis,  on  October  8,  1906,  showed  a  moder- 
ate amount  of  albumin,  no  casts.  Anemia,  edema  of  face  and 
ankles,  indigestion. 

E.  C,  white,  female,  aet.  7,  five  attacks,  last  one  November 
15,  1906;  urinalysis,  December  4,  1906,  nitric  acid  test  for 
albumin  negative,  microscope  showed  a  very  few  cylindroids 
and  hyaline  and  granular- casts. 

R.  A.,  mulatto,  male,  aet.  44,  one  attack  November  13,  1905 ; 
urinalysis,  August  22,  1906,  showed  no  albumin,  moderate 
number  of  cylindroids,  and  a  few  hyaline  casts. 

J.  P.,  white,  male,  aet.  37,  several  attacks,  last  one  September 
21,  1907;  urinalysis,  July  28,  1908,  a  slight  trace  of  albumin,  a 
few  hyaline  casts,  very  few  granular. 

W.  S.,  white,  male,  aet.  42,  one  attack,  which  occurred  Feb- 
ruary, 1905 ;  urinalysis,  June  27,  1908,  no  albumin,  a  few 
cylindroids. 

The  possibilities  of  the  abnormalities  of  urine  and  the  symp- 
toms in  the  cases  being  produced  by  other  causes  than  the 
hemoglobinuria  should  be  borne  in  mind. 

Anemia  and  consequent  debility  and  digestive  disturbances 
are  not  uncommon.  Rare  complications  are :  paraplegia,  tetanic 
convulsions,  purpura  hemorrhagica,  dysentery,  pneumonia, 
pancreatitis,  abscess  of  the  liver,  erysipelas,  parotiditis,  retinal 
hemorrhage,  pleurisy,  and  neuralgia.  The  writer  has  seen 
tonsillitis  once  as  a  complication. 


228  THE   STUDY  OF  MALARIA 

CHRONIC  MALARIA 

There  is  a  great  deal  of  confusion  as  to  what  is  compre- 
hended by  chronic  malaria.  Much  of  this  chaos  is  due  to 
including  the  manifestations  of  malarial  cachexia  with  those 
of  chronic  malaria,  between  which,  however,  there  are  essen- 
tial differences.  Chronic  malaria  implies  a  supply  of  vital 
resistance  equal  to  the  demand;  malarial  cachexia  denotes  an 
exhaustion  of  this  supply.  Chronic  malaria  is  an  antagonistic 
equilibrium  between  parasite  and  host;  cachexia,  a  rupture  of 
equilibrium.  Chronic  malaria  is  a  conflict,  cachexia  a  con- 
quest. The  relation  between  chronic  malaria  and  cachexia  has 
been  fitly  compared  to  that  existing  between  a  compensated 
heart  lesion  and  broken  compensation.  Chronic  malaria  is  an 
active  form  of  malaria,  cachexia  is  a  sequel.  Cachexia  being 
a  sequel,  usually  of  chronic  malaria,  it  may  be  difficult  to  say 
where  the  influence  of  the  latter  ends  and  the  former  begins. 
On  the  other  hand,  it  is  frequently  difficult  or  impossible  to 
differentiate  between  a  relapse  in  chronic  malaria  and  a  re- 
infection. 

For  convenience  of  study,  chronic  malaria  may  be  divided 
into  a  latent  or  passive  stage  and  an  active  stage,  or  stage  of 
relapse. 

It  is  more  frequently  observed  in  children.  It  has  already 
been  shown  that  the  frequency  with  which  children  native  to 
the  soil  are  infected  constitutes  the  true  endemic  index  of  a 
locality. 

Chronic  malaria  may  be  due  to  one  infection,  but  occurring 
chiefly  in  regions  where  repeated  reinfection  is  possible,  it  is 
highly  probable  that  reinfection  is  an  important  factor. 

An  analysis  by  the  writer  of  a  large  number  of  cases  shows 
the  following  results :  Quartan  and  tertian  infections  are  more 
prone  to  relapse  than  estivo-autumnal.  The  percentage  of 
relapses  to  total  number  of  cases  of  quartan,  tertian,  and  estivo- 
autumnal  is,  respectively,  65,  55,  and  45.  The  pertinacity  of 
quartan  may  be  regarded  as  a  conservative  effort  of  nature  to 
perpetuate  the  species.  It  is,  indeed,  remarkable  how  this  form 
of  the  parasite  is  conserved  in  certain  places  where  it  is  so  very 
rare.     However,  the  greater  tendency  to  relapse  shown  by  the 


CLINICAL   HISTORY  229 

benign  infections  is  more  than  counterbalanced  by  the  severity 
of  the  symptoms  of  the  estivo-autumnal  relapses.  Hence  it  is 
undoubtedly  true  that  the  estivo-autumnal  parasites  are  the 
most  important  factors  in  chronic  malaria. 

It  is  the  parthenogenetic  cycle  of  the  parasite  that  is  chiefly 
concerned  in  the  pathogenesis  of  chronic  malaria,  though  the 
asexual  forms  also  have  a  role.  The  parthenogametes  are  the 
parasites  of  the  latent  stage,  the  schizonts  of  the  active  stage. 
Parthenogenesis  is  the  bridge  across  the  gap  caused  by  inter- 
ruption of  the  schizogonic  cycle. 

The  most  frequent  course  is  for  chronic  malaria  to  follow 
one  or  more  acute  attacks.  In  some  instances,  however,  the 
latent  stage  may  precede  the  active.  Thus  it  is  not  extremely 
rare  to  meet  cases  with  evidences  of  chronic  malaria  which 
have  no  history  of  active  manifestations. 

The  latent  stage  of  chronic  malaria  resembles  in  some  re- 
spects a  period  of  incubation;  in  fact,  the  cases  reported 
with  unduly  long  stages  of  incubation  are  doubtless  nothing 
but  latent  stages  of  the  chronic  disease.  During  the  latent 
stage  parasites  may  or  may  not  be  found  in  the  peripheral 
blood. 

Symptoms  during  the  latent  stage  may  be  altogether  absent, 
in  which  case  latency  is  absolute,  or  there  may  be  present  cer- 
tain symptoms,  subjectively  insignificant,  constituting  relative 
latency.  These  symptoms  are  ordinarily  similar  to  the  pro- 
dromata  of  acute  malaria :  malaise,  loss  of  appetite,  aching  of 
the  back  and  legs,  digestive  disorders,  etc.,  together  with 
anemia  and  enlarged  spleen.  Latent  malaria  is  the  source  of 
very  numerous  infections,  and  is  of  the  utmost  importance 
from  the  viewpoint  of  prophylaxis. 

The  duration  of  latency  is  exceedingly  variable.  Relapses 
occur  at  shorter  or  at  longer  intervals. 

Relapses  at  short  intervals  have  been  recognized  since  the 
time  of  Hippocrates.  Later  the  septenary  periods  were  noted 
for  a  tendency  to  show  relapses,  and  this  idea  is  still  largely 
prevalent  among  the  laity.  This  shorter  interval  of  latency 
corresponds  more  or  less  closely  to  the  sexual  cycle  of  the 
parasite  and  to  the  period  of  incubation.    It  is  also  in  harmony 


23O  THE   STUDY   OF   MALARIA 

with  the  law  of  Treille304  and  with  the  studies  of  Cohen305 
upon  the  period  of  freedom  from  paroxysms  following  a  single 
injection  of  quinine.  The  duration  of  this  period  is  from  five 
to  twenty-one  days,  oftenest  from  five  to  ten.  Relapses  at 
shorter  intervals  occasionally  exhibit  a  striking  periodicity. 

Relapses  at  longer  intervals  occur  at  from  one  to  twelve 
months,  exceptionally  longer.  Very  long  periods  of  freedom 
have  been  recorded,  even  up  to  sixty  years.306  Undoubtedly 
many  of  these  are  errors,  due  either  to  mistaken  diagnosis  or 
to  the  occurrence  in  the  interval  of  unrecognized  or  masked 
paroxysms.  However,  periods  as  long  as  three  years  have 
been  reliably  recorded.48 

It  being  clinically  impossible  to  distinguish  between  a  relapse 
and  a  reinfection,  the  writer  has  adopted  Celli's80  rule,  it  being 
equally  adapted  to  the  seasonal  prevalence  of  malaria  in  this 
country.  This  authority  regards  as  a  relapse  every  case  of 
fever  which  repeats  itself  in  the  same  individual  during  the 
epidemic  year  of  malaria,  from  July  of  one  year  to  the  end 
of  the  following  June.  It  is  true  that  this  may  include  some 
cases  of  reinfection,  but  it  is  unquestionably  the  most  practical 
guide  and  eliminates  a  maximum  of  error. 

Secondary  etiologic  influences  play  a  much  more  prominent 
role  in  relapses  than  in  primary  infections.  Of  these  the  most 
important  are  change  of  residence,  fatigue,  abuse  of  alcohol, 
exposure,  and  gastro-intestinal  disturbances.  All  are  familiar 
with  the  frequence  with  which  a  change  of  residence  "brings 
the  malaria  out."  These  influences  are  much  commoner  factors 
in  the  relapses  at  long  intervals  than  in  those  at  shorter  inter- 
vals. 

It  is  ordinarily  the  relapse  that  brings  the  chronic  malarial 
to  the  physician.  The  relapse  may  consist  of  one  or  more 
typic  malarial  paroxysms  or  they  may  be  atypic.  Very  often 
the  first  stage  of  the  paroxysm  is  wanting.  They  may  exhibit 
quotidian,  tertian,  or  quartan  periodicity,  or  may  be  altogether 
irregular.  The  patient  usually  has  an  anemic  tint  and  may,  in 
advanced  cases,  be  jaundiced.  Occasionally  the  complexion 
may  be  earthy,  at  other  times  bronzed.  The  skin  is  dry  and 
often  scaly.    The  eyes  may  be  deep  set ;  they  often  bear  a  hag- 


CLINICAL   HISTORY  23 1 

gard,  restless  expression.  The  patient  appears  aged  beyond  his 
years.  The  condition  of  nourishment  is  poor,  and  there  may 
be  edema  of  the  face  and  feet.  There  are  weakness  of  arms 
and  legs  and  an  indisposition  to  physical  exertion.  The  pulse 
is  accelerated,  weak,  and  sometimes  irregular.  Percussion 
may  reveal  an  increase  in  the  cardiac  dulness,  and  auscultation 
an  anemic  murmur.  Dyspnea  on  slight  exertion,  a  feeling  of 
weight  or  pain  in  the  precordia,  and  palpitation  are  not  infre- 
quent symptoms. 

The  extent  of  the  blood  destruction  depends  upon  the  sever- 
ity and  proximity  of  the  paroxysms  and  the  activity  of  the 
blood-making  organs.  The  number  of  red  cells  frequently 
falls  to  one  million  per  c.mm.  or  even  less.  In  other  cases  the 
destroyed  cells  are  nearly  replaced  within  a  short  time  after 
the  relapse.  The  hemoglobin  percentage  is  sometimes  dispro- 
portionately lower  than  the  red  cell  count,  though  occasionally 
it  may  be  normal  or  above.  The  leukocyte  formula  is  similar 
to  that  of  acute  infections.  Parasites  of  the  asexual  cycle  are 
usually  found  in  the  peripheral  blood.  Tertian  gametes  are 
frequently  seen,  while  quartan  are  rare.  The  frequency  of 
crescents  and  ovoids  is  very  variable.  In  my  experience  they 
are  very  rarely  seen  in  blood  obtained  from  the  superficial 
circulation.  They  are  also  infrequent  in  the  experience  of 
Manson59  (in  cases  seen  in  the  tropics),  A.  Plehn,171  Craig,307 
Stephens  and  Christophers,118  Ziemann,308  Wellman,309  Annett, 
Dutton  and  Elliott,310  Kendall,30  and  others.  The  majority  of 
observers,  however,  have  seen  estivo-autumnal  gametes  in  a 
considerable  proportion  of  their  cases.  In  localities  where  this 
phase  of  the  parasite  is  so  rare  it  is  rather  difficult  to  under- 
stand how  the  species  is  preserved.  The  most  probable  ex- 
planation is  that  the  sexual  cycle  is  supplanted  by  the  partheno- 
genetic  cycle  in  the  perpetuation  of  the  species,  the  partheno- 
gametes  tending  to  congregate  in  the  spleen. 

Other  blood  changes,  as  nucleated  red  cells,  microcytes, 
macrocytes,  and  poikilocytes,  are  more  common  in  chronic  than 
in  acute  malaria. 

The  respiration  is  usually  quickened,  especially  after  exer- 
cise.    Chronic  bronchial  catarrh,  usually  of  a  mild  degree,  is 


232  THE   STUDY   OF   MALARIA 

not  a  rare  condition  in  chronic  malaria,  and  epistaxis  is  some- 
times profuse. 

Digestive  disorders  are  very  common  and  marked  meteorism 
may  exist.  The  condition  of  the  bowels  is  not  constant,  diar- 
rhea sometimes  alternating  with  constipation.  Dysenteric 
manifestations  are  frequent. 

The  spleen  may  be  of  normal  proportions  in  mild  cases,  but 
is  usually  enlarged,  sometimes  enormously  so,  passing  the 
median  line  of  the  abdomen  and  the  iliac  crest.  It  may  or  may 
not  be  tender  or  painful ;  in  the  former  case  the  pairi  is  usually 
of  a  pulling  nature  and  referred  to  the  left  shoulder.  If  peri- 
splenitis with  adhesions  does  not  occur  the  spleen  may  be 
movable  or  floating.  Often  the  spleen  enlarges  during  the 
active  stage  to  recede  slowly  during  latency.  The  liver  is  often 
slightly  enlarged  and  tender. 

Headache,  nervousness,  restlessness,  vertigo,  insomnia,  and, 
in  severe  cases,  impaired  memory,  are  observed.  .  The  urine  is 
often  albuminous. 

Masked  Malaria. — Masked  or  larvate  malaria,  like  perni- 
cious malaria,  needs  complete  overhauling.  Nearly  every  dis- 
ease in  the  category  has  been  confounded  with  malaria  and 
classed  as  larvate.  This  heterogeneous  group  has  been  ex- 
panded to  embrace  diseases  unrelated  in  any  way  to  malaria, 
diseases  complicating  malaria,  and  symptoms  and  sequelae  of 
malaria.  The  frequency  of  masked  malaria  varies  inversely 
with  the  care  employed  in  diagnosis.  Masked  malaria  is  merely 
atypic  malaria.  The  symptoms  being  of  little  value  in  diagno- 
sis, this  must  be  made  by  the  anamnesis,  the  microscopic  ex- 
amination of  the  blood,  and  by  the  therapeutic  test.  Nervous, 
gastro-intestinal,  and  cutaneous  disorders  are  those  most  fre- 
quently recorded  as  masked.  Most  of  these  are  to  be  consid- 
ered under  Complications  and  Sequelae. 

COMPLICATIONS  AND  SEQUELS 

Circulatory  System. — Malaria  is  very  frequently  complicated 
by  heart  disorders.  In  the  negro  population  of  the  South,  in 
whom  syphilis,  abuse  of  alcohol  and  tobacco,  pneumonia,  and 
other  etiologic  factors  are  very  prevalent,  lesions  of  the  cir- 


CLINICAL   HISTORY  233 

culatory  system,  particularly  valvular  lesions  of  the  heart,  often 
add  to  the  gravity  of  severe  malarial  infections.  These  are  to 
be  regarded  almost  invariably  as  complications  and  not  as 
sequela?.  Circulatory  lesions,  the  direct  result  of  malarial  in- 
vasion, are  remarkably  rare.  Many  such  cases  were  reported 
before  the  discovery  of  the  parasite,  but  are  for  this  reason 
practically  valueless. 

Collin227  found  cardiac  hypertrophy  in  6  of  61,  and  Kelsch 
and  Kiener178  in  34  of  80  autopsies  on  malarial  subjects.  It  is, 
however,  by  no  means  certain  that  malaria  was  responsible  for 
the  hypertrophy  in  these  cases. 

Probably  the  commonest  cardiac  sequel  of  malaria  is  myo- 
carditis. Slight  evidences  of  degeneration  of  the  heart  muscle 
are  sometimes  found  after  death  in  cases  which  presented  no 
symptoms  during  life.  Triantaphyllides311  observed  26  cases 
with  symptoms  of  myocarditis  in  12,000  cases  of  malaria ;  these 
cases  he  believes  due  solely  to  malaria.  The  cases  of  so-called 
asthenia  cordis  following  malaria  are  probably  cases  of  myo- 
carditis. Dilatation  may  follow  myocarditis.  Localizations  of 
parasites  in  the  blood-vessels  of  the  heart  have  been  mentioned 
when  considering  pernicious  malaria. 

Angina  pectoris  is  occasionally  observed  in  connection  with 
malaria.  It  may  exist  as  a  complication  or  as  the  cardialgic 
type  of  pernicious  malaria. 

Much  was  formerly  written  about  malarial  endocarditis, 
aortitis,  and  endarteritis.  These  occur  but  rarely  and  only  as 
complications.  Ulcerative  endocarditis  has  occasionally  been 
observed  after  pneumonia  complicating  malaria.  It  should  be 
borne  in  mind  that  the  temperature  of  septic  endocarditis  may 
be  similar  to  that  of  malaria.  Pericarditis  and  aortic  aneurism 
are  unusual  complications.  Phlebitis  and  thrombosis  have  been 
seen,  more  often  in  cases  of  cachexia. 

There  is  absolutely  no  evidence  that  malaria  is  a  causative 
factor  in  either  lymphangitis  or  lymphadenitis,  the  so-called 
malarial  bubo,  these  conditions  occurring  only  as  complica- 
tions. A  suppurating  bubo,  like  other  septic  processes,  may 
be  accompanied  by  an  intermittent  temperature. 

Respiratory  System. — Coryza  may  occur  as  a  complication 


234  THE   STUDY   OF   MALARIA 

to  malaria,  especially  during  unseasonable  weather.  Bronchitis 
is  a  common  complication,  during  a  portion  of  the  malarial 
season  occurring  with  marked  frequency.  It  is  observed 
oftener  in  the  negro  than  in  the  white  race.  Subacute  or 
chronic  bronchitis  is  usually  in  chronic  malaria  and  cachexia. 

Ziemann  reports  the  case  of  a  healthy  young  man  who,  dur- 
ing an  attack  of  estivo-autumnal  malaria,  was  afflicted  with 
intermittent  spasm  of  the  laryngeal  muscles.  The  spasms 
coincided  with  the  malarial  paroxysms,  parasites  were  found 
in  the  blood,  and  both  the  malaria  and  the  laryngeal  trouble 
yielded  promptly  to  quinine. 

A  peculiar  condition  of  the  pulmonary  apices  has  been  de- 
scribed. It  consists  of  a  rapid  and  a  transient  congestion  of 
the  apex  of  one  or  both  lungs,  arising  and  disappearing  with 
the  paroxysm.  The  cough  is  dry  and  painful,  the  expectoration 
is  scanty,  occasionally  bloody,  and  there  may  be  bronchial 
breathing  and  increased  vocal  fremitus.  The  writer  has  had 
no  experience  with  this  complication. 

Pneumonia  was  long  considered  a  manifestation  or  a  sequel 
of  malaria,  but  it  is  now  known  that  they  are  entirely  distinct 
diseases. 

Either  lobular  or  lobar  pneumonia  may  complicate  malaria, 
the  latter  more  frequently  than  the  former.  Lobar  pneumonia 
sometimes  occurs  with  acute  malaria,  but  much  more  com- 
monly with  chronic  malaria  and  cachexia.  It  is  probably  the 
most  frequent  mode  of  exit  of  the  cachectic,  in  whom  the 
pneumonia  often  assumes  the  low  form  and  is  especially  liable 
to  complications,  as  delayed  resolution,  gangrene,  abscess,  and 
pyothorax.  Pneumonia  complicating  malaria  is  apt  to  be 
atypic,  though  the  pneumonic  symptoms  usually  predominate. 
Both  lungs  are  more  apt  to  be  affected,  profuse  hemoptosis 
occasionally  occurs,  and  malarial  parasites  may  be  found  in 
the  expectorated  blood.  Fibroid  pneumonia  sometimes  com- 
plicates malarial  cachexia.  The  prognosis  in  malaria  compli- 
cated with  pneumonia  is  grave. 

Pleurisy  is  not  a  common  complication  of  paludism.  It  has 
been  maintained312  that  the  enlarged  spleen,  especially  if  peri- 
splenitis exists,  predisposes  to  inflammation  of  the  left  pleura. 


CLINICAL   HISTORY  235 

but  this  requires  further  evidence.  Hydrothorax  may  rarely 
be  present  in  cachexia.  Jenness313  has  recently  recorded  a  fatal 
case  of  abscess  of  the  right  diaphragmatic  pleura  during  an 
attack  of  tertian  malaria.  The  chief  physical  signs  were  flat- 
ness on  percussion,  and  absence  of  respiratory  and  voice 
sounds;  there  was  no  bulging  of  the  chest  wall.  At  autopsy 
the  liver  was  found  normal. 

Gastro-intestinal  Tract. — Stomatitis  is  sometimes  observed 
in  malaria.  Parotitis  is  an  infrequent  complication.  Dyspeptic 
symptoms  denoting  chronic  gastric  catarrh  are  not  uncom- 
mon in  cases  of  chronic  malaria  and  cachexia.  Gastric  ulcer 
in  association  with  amyloid  changes  in  the  mucosa  is  rarely 
noted.  Hematemesis  occasionally  assumes  alarming  propor- 
tions. 

Enteritis  is  a  much  more  frequent  sequela  of  malaria  than 
ordinarily  regarded.  The  inflammation  may  advance  to  ulcera- 
tion. The  process  has  been  frequently  demonstrated  by  autop- 
sies to  be  due  to  accumulations  of  parasites  in  the  intestinal 
mucosa.  Diarrhea  is  common,  especially  in  persons  improperly 
fed.  Profuse  hemorrhage  occasionally  occurs,  in  which  case 
the  microscopic  examination  of  the  blood  is  of  the  greatest 
value  in  differentiating  the  disease  from  typhoid  fever. 

Dysenteric  symptoms  arising  in  the  course  of  malaria  and 
the  dysenteric  form  of  pernicious  malaria  have  been  consid- 
ered. Well-marked  dysentery  may  be  present  either  as  a  com- 
plication or  as  a  sequela.  Often  the  dysenteric  symptoms  pre- 
dominate, thus  constituting  one  of  the  commonest  forms  of 
masked  malaria.  Craig164  has  shown  that  65  per  cent,  of  the 
patients  with  malarial  parasites  in  the  blood  observed  at  the 
Army  General  Hospital,  Presidio  of  San  Francisco,  suffered 
at  some  time  from  acute  or  chronic  dysentery,  and  of  these 
more  than  25  per  cent,  suffered  from  amebic  dysentery. 
Thayer98  says  that  nearly  12  per  cent,  of  the  cases  of  amebic 
dysentery  treated  at  the  Johns  Hopkins  Hospital  have  suffered 
simultaneously  with  malaria.  In  36  cases  of  dysentery  asso- 
ciated with  malaria  Ewing27  found  the  Amoeba  dysenterica  in 
the  stools  of  9.  Dysentery  aggravates  the  prognosis  of  malaria. 

Besides  the  ameba,  other  intestinal  parasites  may  complicate 


236  THE   STUDY   OF  MALARIA 

paludism.  Of  these  by  far  the  most  common  is  the  Ascaris 
lumbricoides.  Uncinariasis  is  not  an  infrequent  complication 
in  some  sections.  The  writer  has  observed  an  infection  with 
Hymenolepis  nana  associated  with  malaria.  It  is  not  improba- 
ble that  intestinal  helminthiasis  aggravates  the  anemia  and 
the  gastro-intestinal  and  nervous  symptoms.  In  examining 
the  blood  for  the  malarial  parasite  the  presence  of  eosinophilia 
calls  for  an  examination  of  the  feces. 

Cirrhosis  of  the  liver,  the  direct  result  of  malarial  infection, 
described  as  relatively  frequent  in  certain  portions  of  the 
tropics,  appears  to  be  rare  in  this  section.  Hypertrophic 
hepatitis  may  result  from  prolonged  infection.  Ascites  occa- 
sionally develops,  particularly  in  chronic  malaria  and  cachexia. 

The  Blood  and  Spleen. — Leukemia  follows  malaria  only 
rarely,  probably  never  as  a  true  sequela.  In  124  cases  of  leuke- 
mia Mosler79  determined  that  only  8  or  10  bore  any  etiologic 
relation  to  malaria.  Marchiafava  and  Bignami22  observed  a 
case  of  splenomedullary  leukemia  in  an  adult  male,  aged 
twenty-eight.  The  symptoms  were  enormous  enlargement  of 
the  spleen  and  liver,  diarrhea,  and  grave  anemia.  The  case 
had  been  diagnosed  malarial  cachexia.  Bastianelli67  observed  a 
similar  case.  Ziemann48  treated  a  case  in  the  ten-year-old 
daughter  of  a  Duala  chief;  the  girl  had  suffered  repeated  at- 
tacks of  malaria,  and  pigmented  leukocytes  were  found  in  the 
blood.  Sakorraphos79  described  10  cases  of  leukemia  in  per- 
sons who  had  formerly  lived  in  malarial  localities.  However, 
the  blood  examination  showed  no  parasites  nor  was  there  any 
elevation  of  the  temperature.  Brown79  saw  a  case  of  lymphatic 
leukemia  follow  malaria.  The  writer  has  had  no  experience 
favoring  an  etiologic  relation  between  leukemia  and  malaria. 

The  relation  of  splenic  anemia  (Banti's  disease)  to  malaria 
is  not  clear.  Two  of  Hemmeter's314  cases  followed  malaria, 
and  of  15  which  Osier316  observed  malaria  preceded  5.  Cohen 
and  Rosenberger315  observed  a  case  of  chronic  malarial  infec- 
tion with  spleen  and  blood  lesions  Closely  resembling  those  of 
Banti's  disease.  Injections  of  quinine  and  urea  were  used  with 
good  results.  Splenic  anemia  may  come  into  consideration  in 
differential  diagnosis. 


CLINICAL   HISTORY  237 

Malarial  Cachexia. — In  this  condition  the  parasites  have 
obtained  undisputed  possession  of  the  host.  The  defensive 
forces  have  been  completely  conquered,  the  blood-making  or- 
gans can  no  longer  meet  the  demands  made  upon  them,  and 
toxins,  unopposed,  work  changes,  often  irreparable,  in  impor- 
tant organs.  Cachexia  has  been  classified  as  dry  or  humid, 
according  to  the  absence  or  presence  of  anasarca,  and  as  acute 
or  chronic.  Acute  cachexia  is  characterized  by  a  rapid  onset 
and  development  of  symptoms,  and  usually  follows  acute  mala- 
ria, occasionally  after  only  one  or  two  attacks.  These  cases 
are  infrequent.  Chronic  cachexia,  the  usual  form,  is  a  sequela 
of  chronic  malaria. 

Malarial  cachexia  is  found  where  the  severe  forms  of  mala- 
ria are  endemic.  It  may  be  stated  as  a  general  rule  that  the 
frequency  of  cachexia  among  the  white  race  is  an  index  to  the 
prevalence  of  grave  infections.  It  is  much  more  common  in 
the  white  race  than  in  the  negro.  While  negro  children  are 
not  infrequently  the  subjects  of  malarial  cachexia,  it  is  much 
rarer  in  the  adult  negro.  Of  adults,  males  are  more  commonly 
cachectic  than  females ;  among  children  the  proportion  is  about 
even.  The  condition  rarely  develops  in  persons  of  the  better 
class,  but  is  seen  in  those  living  under  improper  hygienic  con- 
ditions and  who  neglect  the  treatment  of  acute  malaria. 

Cases  of  cachexia  developing  without  preceding  malaria  have 
been  reported,  but  are  subject  to  question.  The  malaria  may 
have  been  unrecognized,  as  might  happen  with  latent  or  masked 
infections.  In  regions  where  kala-azar  is  endemic  it  is  only 
recently  that  this  disease  has  been  differentiated  from  malarial 
cachexia.  Infections  with  the  estivo-autumnal  parasites  are 
followed  by  cachexia  much  more  frequently  than  tertian  and 
quartan  infections. 

The  cachectic  usually  presents  a  singular  appearance.  The 
emaciated  limbs  are  in  marked  contrast  to  the  big  belly,  and 
the  features  are  aged  beyond  the  years.  The  most  pronounced 
phenomena  are  the  anemia  and  the  enlarged  spleen.  The  red 
blood-cells  may  be  reduced  to  seven  or  eight  hundred  thousand 
per  c.mm.  The  leukocytes  are  generally  normal  in  number 
or  a  little  below.     Numerous  differential  counts  have  shown  a 


238  THE   STUDY   OF  MALARIA 

relative  increase  of  the  large  mononuclear  elements.  The  red 
cells  may  show  basophile  degeneration,  polychromatophilia, 
poikilocytosis,  and  nuclei,  but  none  of  these  changes  are  by 
any  means  constant.  According  to  my  experience  parasites 
are  rarely  found  in  the  peripheral  blood.  The  spleen  often 
extends  to  the  umbilicus  and  to  the  crest  of  the  ilium,  some- 
times beyond.  It  is  usually  hard  and  the  anterior  border  pre- 
sents a  sharp  edge.  Pain  and  tenderness  on  pressure  are  not 
always  felt.  Occasionally  a  bruit  is  to  be  detected  over  the 
splenic  area. 

The  pulse  is  small,  compressible,  and  may  be  irregular.  Pal- 
pitation of  the  heart  and  hemorrhages,  especially  epistaxis, 
may  occur.  An  anemic  murmur  over  the  precordia  is  often 
heard.  Myocarditis  and  dilatation  are  not  infrequent.  The 
breath  is  short,  sometimes  amounting  to  actual  dyspnea.  A 
cough  is  common  and  signs  of  bronchitis  may  be  elicited.  Pul- 
monary edema  is  a  late  symptom. 

The  temperature  may  be  normal  or  subnormal  for  long 
periods,  though  evening  rises  are  often  observed.  Typic  parox- 
ysms are  not  frequent.  Fever  often  follows  imprudences. 
Whether  the  fever  of  cachexia  is  due  directly  to  parasitic  activ- 
ity or  to  organic  changes  is  not  definitely  known.  The  appetite 
is  generally  poor  and  the  digestion  tardy.  Epigastric  pain, 
nausea,  and  vomiting  may  be  complained  of.  The  tongue  and 
oral  mucous  membrane  are  pale.  Diarrhea  and  dysentery  fre- 
quently occur.  Meteorism  is  common.  The  liver  is  usually 
somewhat  enlarged  at  first;  later  it  may  become  atrophic. 
Ascites  is  not  a  rare  manifestation.  When  fever  exists  the 
urine  is  ordinarily  scanty  and  highly  colored.  Delayed  de- 
velopment of  the  genitals  is  common  in  the  young  and  dimin- 
ished sexual  power  is  not  rare  in  the  adult.  Indifference,  intel- 
lectual torpor,  somnolence,  headache,  and  vertigo  are  observed 
in  cachectics.  Resistance  to  cold  is  lessened  and  rheumatic 
pains  are  experienced.  The  skin  is  pallid,  dry,  and  rough,  and 
may  exhibit  sores  or  purpuric  spots.    Anasarca  may  supervene. 

Pneumonia,  dysentery,  hemoglobinuric  fever,  and  nephritis 
are  common  complications  of  cachexia,  and  amyloid  degenera- 
tion, especially  of  the  kidneys,  an  occasional  sequela.     Peri- 


h 


I'- 

K 

ve 

<L> 

fcC 

(J 
rfS 

Tt, 

U 

CLINICAL   HISTORY  239 

splenitis  occasionally  occurs  and  may  be  the  cause  of  severe 
pain,  especially  if  adhesions  take  place.  A  heavy  spleen  may 
cause  relaxation  of  its  supports  and  become  "floating"  or  "wan- 
dering." This  condition  is  seen  more  often  in  multiparous 
females.  By  pressure  on  neighboring  organs  a  wandering 
spleen  may  cause  pain,  digestive  disorders,  or  even  intestinal 
occlusion.  The  pedicle  may  become  twisted,  as  occurred  in  a 
fatal  case  of  Marchiafava  and  Bignami.22 

Rupture  of  the  spleen  is  an  infrequent  complication  of  mala- 
rial cachexia.  It  is  very  rarely  associated  with  acute  malaria, 
though  a  case  has  been  recorded  by  Palmer317  in  which  rupture 
occurred  within  seven  days  of  the  onset  of  the  fever.  The 
writer  observed  a  case  in  a  subject  of  cachexia  who  had  a 
large,  hard  spleen.  Recovery  followed,  notwithstanding  ex- 
tensive hemorrhage.  In  some  countries,  especially  in  India, 
rupture  of  the  spleen  has  assumed  medicolegal  importance. 
According  to  Brault,318  it  is  popularly  known  in  Kharkov  that 
the  malarial  spleen  is  very  friable,  and  that  combatants  engaged 
in  fist  fights  strive  to  strike  the  region  of  the  spleen,  with  the 
result  that  5  per  cent,  of  the  official  autopsies  show  ruptures 
of  this  organ.  The  rupture  may  be  spontaneous  or  the  result 
of  blows  and  falls.  Of  19  cases  of  rupture  of  the  malarial 
spleen  collected  by  Messerer319  15  were  spontaneous  and  only 
4  the  result  of  trauma.  However,  35  cases  studied  by  Russell95 
were  due  to  trauma,  and  no  cases  of  spontaneous  rupture  were 
noted.  A  large,  soft  spleen  is  much  more  liable  to  rupture  than 
a  hard  one,  and  fatal  hemorrhage  is  more  apt  to  occur  in  the 
former  case.  A  full  stomach  predisposes  to  splenic  rupture, 
especially  of  the  concave  side.  The  capsule  is  usually  ruptured, 
but  when  thickened,  as  may  result  from  previous  perisplenitis, 
it  may  escape  untorn.  The  capsule  was  not  ruptured  in  only 
1  of  Russell's95  35  cases.  The  laceration  occurs  with  about 
equal  frequency  on  the  concave  and  convex  sides  of  the  spleen. 
Tears  of  the  inner  aspect  may  occur  without  marks  of  violence 
of  either  the  skin  or  the  convex  surface  of  the  spleen.  A  light, 
sharp  blow  tends  to  injure  the  convex  surface ;  a  fall  or  crush- 
ing blow,  the  concave  side.  The  symptoms  of  rupture  of  the 
spleen  consist  of  violent  pain  in  the  splenic  region  referred  to 


240  THE   STUDY   OF   MALARIA 

the  left  shoulder,  together  with  evidences  of  shock  and  hemor- 
rhage. The  mortality  of  cases  not  treated  with  splenectomy 
is  exceedingly  high.  Death  may  occur  in  from  a  few  hours 
to  five  days. 

Abscess  of  the  spleen  is  a  rarer  complication  of  malaria  even 
than  rupture.  The  writer  is  able  to  collect  from  the  literature 
mention  of  not  more  than  50  cases.  The  common  pyogenic 
cocci  and  the  bacillus  coli  communis  are  the  bacteria  usually 
present  in  splenic  abscesses.  The  symptoms  are  sometimes  as 
vague  as  those  of  abscess  of  the  liver.  There  may  be  pain  in 
the  left  hypochondrium,  especially  if  the  abscess  is  superficial 
and  the  peritoneum  is  involved.  The  pain  is  often  referred  to 
the  left  shoulder.  Pain  may,  however,  be  entirely  wanting. 
The  temperature  is  usually  elevated,  though  in  rare  instances 
may  be  normal  or  subnormal.  It  is  usually  intermittent  and 
associated  with  chills  and  sweats.  Emaciation  may  be  extreme, 
notwithstanding  the  appetite  is  sometimes  voracious.  Abscess 
of  the  spleen  may  be  confused  with  uncomplicated  malaria,  and 
renal,  gastric,  or  pancreatic  disease.  The  presence  of  leuko- 
cytosis and  the  therapeutic  test  are  valuable  diagnostic  points. 
Signorelli's  spleen  point  may  be  a  useful  guide.  This  is  a 
painful  area  corresponding  to  the  fifth  intercostal  space  near 
the  left  nipple.  The  examination  of  the  urine  may  mislead. 
In  a  case  of  splenic  abscess  observed  by  Goltman320  the  urine 
contained  albumin,  casts,  pus  cells,  renal  cells,  and  some  red 
blood-cells.  Aspiration  is  attended  with  some  danger,  but  may 
be  done  as  a  last  resort,  especially  if  the  patient  is  prepared  for 
operation.  The  abscess  may  rupture  externally  into  the  pleural 
cavity  or  lung  of  the  left  side,  or  into  the  stomach,  intestine,  or 
peritoneal  cavity.  Without  operation  the  prognosis  is  very 
grave;  with  timely  incision  and  drainage  a  considerable  per 
cent,  recover. 

Infarcts  and  gangrene  of  the  spleen  are  noted  among  the 
rare  complications  of  the  spleen  in  malarial  cachexia. 

Genito-urinary  Organs.  Nephritis. — The  frequency  of  nej 
phritis  recorded  as  a  sequela  of  malaria  varies  greatly  with 
locality,  type  of  fever,  and  with  the  idea  of  what  constitutes 
nephritis.     Thus,   while  Ford180   observed  acute  nephritis  in 


CLINICAL   HISTORY  241 

only  1.5  per  cent,  of  his  cases  of  malaria,  Moore321  reports  the 
percentage  as  80.  The  real  frequency  of  nephritis  in  malaria 
is  in  about  /2  to  2  per  cent,  of  the  cases  of  tertian  and 
quartan  infections  and  2  to  5  per  cent,  in  estivo-autumnal.  The 
negro  is  apparently  more  susceptible  to  the  renal  lesions  of 
malaria  than  is  the  white.  More  cases  are  seen  in  the  months 
during  which  the  estivo-autumnal  fevers  prevail.  The  middle- 
aged  and  the  old  are  less  often  attacked  than  the  young. 
Nephritis  is  much  more  prone  to  result  from  chronic  than 
from  acute  malaria.  The  nephritis  is  most  often  acute,  but 
it  is  highly  probable  that  malaria  is  an  important  factor  in  the 
etiology  of  chronic  nephritis.  Chronic  nephritis  may  follow 
the  acute  form  or  may  exist  as  such  from  the  beginning.  True 
hemorhagic  nephritis  is  rare.  There  is  ordinarily  nothing  char- 
acteristic either  in  the  symptoms  or  pathologic  histology  of  the 
nephritis  of  malaria.  Ewing,177  however,  has  observed  an  in- 
teresting and  unique  case  of  malarial  nephritis  with  extensive 
massing  of  the  parasites  in  the  kidneys.  Parenchymatous  ne- 
phritis is  the  commonest  type,  though  the  contracted  kidney 
may  occur  as  a  late  lesion.  Kelsch  and  Kiener178  divide  mala- 
rial nephritis  into  the  diffuse  or  glomerular  and  the  granular 
nephritis  of  Bright,  each  with  acute  and  chronic  forms.  Amy- 
loid degeneration  is  a  renal  sequela  of  malaria. 

Occasionally  intense  lumbar  pain,  closely  simulating  renal 
colic,  is  experienced  as  a  complication  of  malaria.  This  colic 
usually  responds  promptly  to  quinine,  though  the  pathogenesis 
is  not  clear. 

Forms  of  orchitis  and  epididymitis  have  for  a  long  time  been 
attributed  to  malaria.  Either  may  complicate  malaria.  The 
writer  has  seen  several  cases  of  epididymitis  associated  with 
malaria,  there  being,  however,  in  each  case  a  history  of  venereal 
disease.  There  is  at  the  present  time  absolutely  no  evidence 
that  either  orchitis  or  epididymitis  is  ever  a  true  sequela  of 
malarial  disease.  The  same  may  be  said  of  hydrocele,  which 
some  observers  have  ascribed  to  malaria. 

It  is  doubtful  whether  genuine  atrophy  of  the  testicles  ever 
occurs  as  the  result  of  malaria.  It  is  more  probable  that  these 
cases  are  due  to  improper  development,  the  result  of  cachexia, 

16 


242  THE   STUDY   OF   MALAEIA 

climate,  or  other  factors.  Duprey322  has  recently  described 
three  cases  of  impotence  following  estivo-autumnal  fever. 
Metrorrhagia  and,  more  often,  menorrhagia  and  amenorrhea 
are  not  infrequently  seen  with  malaria.  Sterility  has  been 
charged  to  paludism. 

It  was  formerly  believed  that  pregnancy  conferred  a  degree 
of  immunity  against  malaria.  This  is  now  known  not  to  be 
true.  If  the  pregnant  woman  is  attacked  less  often  with 
malaria  it  is  because  she  is  less  often  exposed  to  infection  and 
not  on  account  of  any  immunity  which  pregnancy  confers  upon 
her. 

A  list  of  cases  is  appended  to  give  an  idea  of  the  frequency 
with  which  abortion  and  premature  labor  occur  as  the  result 
of  malaria  complicating  pregnancy.  The  first  column  of  fig- 
ures records  the  number  of  cases  in  which  the  complication 
appeared;  the  second  column  shows  the  number  of  abortions 
and  premature  labors  which  occurred : 

Pascali105    ; 34  25 

Weatherly,159  in  India 88  28 

Weatherly,169  in  England 58  2 

Weatherly,159  in  Africa 97  22 

Weatherly,159  in  Florida 52  22 

Hospital,    Rome88 51  33 

Lwow323    26  10 

Goth324  46  19 

Bonfils325  105  73 

Williams326   _I5  

572  234 
24.4  per  cent. 

This  percentage  is  at  least  twice  as  large  as  that  resulting 
from  my  experience. 

The  writer  is  inclined  to  the  belief  that  the  negro  is  much 
less  liable  to  suffer  abortion  or  premature  delivery  than  is  the 
white.  This  is  in  keeping  with  the  well-known  relative  im- 
munity of  the  negro  to  some  of  the  effects  of  malaria.  Mer- 
cier182  has  observed  an  unusually  large  number  of  abortions  in 
Creole  women  infected  with  malaria.  It  is  well  known  that 
this  race  is  markedly  susceptible,  to  the  severer  forms  of 
malaria. 

Cases  accompanied  by  continued  high  temperature,  retching, 
and  vomiting,  and  which  are  more  resistent  to  treatment,  are 


CLINICAL    HISTORY  243 

those  in  which  abortion  most  frequently  occurs.  Hence  it 
follows  that  abortion  is  more  often  due  to  estivo-autumnal 
fever  than  to  tertian  and  quartan,  and  to  multiple  infections 
than  to  single. 

The  danger  of  abortion  and  premature  delivery  is  greater 
in  proportion  as  the  pregnancy  is  advanced.  Thus  of  Goth's324 
19  cases  expulsion  of  the  uterine  contents  occurred:  once  in 
the  fourth  month,  once  in  the  fifth  month,  three  times  in  the 
sixth  month,  five  times  in  the  seventh  month,  and  nine  times 
in  the  eighth  month. 

The  factors  in  the  interruption  of  pregnancy  are  probably 
fever,  retching,  vomiting,  anemia,  and  toxins.  It  is  not  im- 
improbable  that  in  some  cases  parasitic  localizations  in  the 
uterine  vessels  excite  pains  or  cause  placental  separation, 
though  for  this  theory  there  is  as  yet  no  pathologic  proof. 

If  the  malarial  infection  does  not  terminate  the  pregnancy 
the  labor  at  full  term  is  apt  to  be  slow,  especially  the  first  stage. 

Children  born  at  full  term  of  malarial  mothers  are  apt  to  be 
smaller  and  lighter  than  normal,  and  the  mortality  is  higher. 

Labor  often  rekindles  latent  malaria,  which,  in  the  puer- 
perium,  is  not  infrequently  atypic,  the  first  or  third  stages  of 
the  paroxysm  or  complete  intermission  of  the  temperature 
sometimes  lacking.  Subinvolution,  postpartum  hemorrhage, 
and  suppression  of  milk  may  occur  with  puerperal  malaria. 

Nervous  System. — It  is  often  impossible  to  determine 
whether  nervous  manifestations  in  malaria  are  complications 
or  sequelae.  It  is  certain  that  many  cases  reported  as  due  to 
malaria  are  purely  complications.  This  is  the  case  with  mul- 
tiple neuritis,  of  which  numerous  cases  have  been  ascribed  to 
malaria.  In  by  far  the  majority  of  cases  the  existence  of 
malaria  was  not  established  by  blood  examination;  in  others 
it  is  not  certain  that  the  neuritis  was  due  to  malaria. 

Glogner,327  in  the  East  Indies,  described  6  cases  of  polyneu- 
ritis occurring  during  and  after  malarial  disease.  In  4  cases 
the  parasites  were  found  in  the  blood.  The  chief  symptoms 
were  diffuse  pains  in  the  lower  limbs,  formication,  tenderness 
of  the  nerves  and  muscles,  and  motor  weakness,  while  the  deep 
reflexes  were  sometimes  intact,  sometimes  abolished.    The  elec- 


244  THE   STUDY   OF   MALARIA 

trie  excitability  of  the  nerves  and  muscles  was  diminished, 
while  sensibility  was  retained.  Edema  of  the  legs  was  present 
in  some  of  the  cases. 

Price328  records  a  case  in  a  girl,  eight  years  old,  who  fol- 
lowing malarial  infection,  had  multiple  neuritis  which  lasted 
eighteen  months.  Her  symptoms  were  pain,  paresthesia,  hand 
tremor,  weakness  of  the  extremities,  with  characteristic  foot 
drop.  Estivo-autumnal  parasites  were  detected  on  blood  ex- 
amination, and  quinine  effected  a  cure. 

Ziemann48  observed  a  case  of  peripheral  neuritis  in  a  young 
German  merchant  who  had  been  in  Cameroon  four  months. 
Two  days  before  his  entrance  into  the  hospital  he  was  taken 
with  high  fever  without  a  preceding  cold  stage.  Simultane- 
ously he  noted  almost  complete  paralysis  of  both  legs,  espe- 
cially of  the  right.  Neither  the  bladder  nor  bowel  functions 
were  affected,  nor  was  there  marked  sensory  disturbance. 
The  temperature  did  not  exceed  103.5°  F.  The  peripheral 
blood  showed  an  enormous  number  of  estivo-autumnal  para- 
sites. While  the  paralysis  of  the  left  leg  persisted  only  a  few 
days  during  convalescence,  that  of  the  right  leg  was  slow  in 
diminishing,  notwithstanding  massage  and  electric  treatment 
for  several  weeks,  so  that  at  the  end  of  four  months  the  patient 
was  still  compelled  to  walk  with  the  aid  of  a  stick. 

It  is  not  infrequently  difficult  to  differentiate  between  poly- 
neuritis and  myelitis. 

Laveran1  describes  a  case  of  paraplegia  which  he  observed  in 
Constantine.  The  patient  had  had  several  attacks  of  malaria 
and  underwent  a  relapse  after  admission  to  the  hospital,  during 
which  the  parasite  was  found  on  microscopic  examination. 
The  paralysis  of  the  lower  limbs  was  not  accompanied  by  any 
alteration  of  sensibility  nor  of  nutrition,  and  micturition  and 
defecation  were  normal.  Unfortunately  for  an  exact  diagnosis 
the  patient  had  had  syphilis  also.  Mercury  and  potassium 
iodide  were  prescribed  without  appreciable  result.  Quinine 
caused  a  disappearance  of  the  parasites,  but  had  no  effect  on 
the  paralysis. 

A  fatal  case  showing  paraplegia  was  treated  by  Ziemann.48 
The  patient  was  a  strong  negro  man.     Bladder  paralysis,  re- 


CLINICAL   HISTORY  245 

tention  of  urine,  and  coma  were  present.  The  blood  contained 
estivo-autumnal  parasites. 

Da  Costa's329  case  of  paraplegia  harbored  the  estivo-autumnal 
parasite  and  yielded  to  quinine. 

Either  persistent  or  intention  tremors  may  be  associated 
with  paludism.  The  case  of  Da  Costa  just  mentioned  exhibited 
intention  tremor.  Fornaca330  reports  a  case  in  a  peasant,  aged 
fifty-seven,  whose  personal  and  family  history  were  good  and 
who,  during  an  attack  of  malaria,  was  affected  with  tremors 
of  both  arms  and  hands.  These  tremors  were  irregular  and 
increased  on  voluntary  motion,  but  did  not  cease  during  rest. 
They  became  exaggerated  during  the  paroxysm  and  diminished 
in  the  interim.  Simple  tertian  parasites  were  present  in  the 
blood  and  the  symptoms  disappeared  upon  the  administration 
of  quinine. 

Torti331  saw  2  cases  in  which  there  were  symptoms  of  multi- 
ple sclerosis  without  a  history  of  syphilis  or  the  abuse  of  alcohol 
or  tobacco.  In  both  cases  parasites  were  found,  and  both  were 
cured  with  quinine. 

Spiller332  has  reported  a  case  closely  resembling  multiple 
sclerosis.  The  patient,  a  male,  aged  forty,  gave  a  history  of 
having  had  a  chancre  twenty  years  before.  He  came  under 
observation  three  years  before  death,  which  resulted  from 
acute  diarrhea,  lasting  one  week  and  probably  of  malarial 
origin.  The  symptoms  were  a  very  decided  intention  tremor 
of  the  left  upper  limb;  marked  ataxia  of  the  left  lower  limb; 
alternating  hemiparesis,  first  of  one  side  of  the  body,  then  of 
the  other;  headache,  drowsiness,  vertigo,  and  diplopia;  marked 
vertical  nystagmus ;  scanning  speech ;  exaggerated  tendon  re- 
flexes and  ankle  clonus  on  the  right  side.  Post  mortem  the 
spleen  was  found  to  weigh  550  grams.  The  crossed  pyramidal 
tract  was  moderately  sclerotic  throughout  the  cord;  this 
sclerosis  could  be  traced  as  high  as  the  left  internal  capsule. 
All  the  capillaries  of  the  brain  and  cord  were  filled  with  estivo- 
autumnal  parasites,  and  numerous  small  and  recent  hemor- 
rhages were  seen  in  the  left  paracentral  lobule  and  other  por- 
tions of  the  cortex.  The  capillaries  observed  under  a  low- 
power  lens  appeared  to  have  been  injected  with  black  powder. 


246  THE   STUDY  OF  MALARIA 

The  sclerotic  lesions  are  said  not  to  have  resembled  those  due 
to  syphilis,  and  the  symptoms  are  believed  to  have  been  due 
to  the  parasitic  thromboses  of  the  capillaries  and  not  to  the 
sclerosis. 

Hemiplegia,  paraplegia,  and  various  monoplegias,  either  with 
or  without  aphasia  or  sensory  disturbances,  are  not  infre- 
quently associated  with  malaria. 

Cerebellar  syndromes  are  rarely  observed  in  malaria.  They 
consist  of  general  weakness,  rigidity,  and  pain  in  the  back  of 
the  neck,  intense  headache,  ataxic  gait  with  a  tendency  to  fall 
backward  and  to  the  left,  tremors,  incoordination  of  move- 
ment, dysarthria,  nystagmus,  and  vomiting.  The  tertian  para- 
site is  usually  present  in  these  cases. 

Bulbar  symptoms  are  occasionally  encountered.  Such  are 
hypoglossal  and  facial  paralysis,  ataxia  of  arm,  dysarthria  or 
anarthria,  and  staggering  gait.  These  symptoms  are  usually 
obstinate. 

Various  psychoses  occur  in  connection  with  malaria,  either 
during  or  following  acute  or  chronic  malaria.  The  commonest 
of  these  disorders  are  weakened  memory,  melancholia,  mania, 
and  delusional  insanity.  Suicidal  and  erotic  tendencies  may 
be  observed.  Below  are  brief  notes  on  4  cases  under  the  care 
of  Ziemann333  in  Cameroon : 

1.  A  merchant,  thirty-six  years  of  age,  slender,  pale,  with 
a  history  of  neurasthenia  but  not  of  alcoholism,  living  in  a  very 
unhealthy  locality,  but  using  no  prophylactic  quinine,  having 
had  several  moderate  and  light  attacks  of  estivo-autumnal 
fever,  was  suddenly  seized  with  a  violent  paroxysm.  During 
the  seizure  he  had  strong  delusions  of  persecution.  He  seized 
his  gun  in  order  to  shoot  down  the  neighbors  whom  he  thought 
pursuing  him.  Energetic  quinine  therapy  was  followed  by 
complete  cure  excepting  that  the  idea  that  the  neighbors  had 
persecuted  him  during  the  night  of  his  illness  persisted. 

2.  A  strong  young  merchant,  with  no  hereditary  taint  nor 
alcoholic  history,  not  having  employed  quinine  prophylactically, 
had  an  attack  of  estivo-autumnal  malaria.  During  the  access 
he  distinctly  heard  the  voices  of  his  father  and  other  relatives 
in  Europe,  and  conversed  with  them  upon  his  prospects  in 


CLINICAL   HISTORY  247 

Cameroon.  Complete  cure  followed  the  administration  of 
quinine  except  the  fixed  idea  that  his  relatives  had  visited  him 
during  his  illness  and  that  he  was  more  quiet,  peculiar,  and 
neurasthenic.  He  was  returned  home  on  the  failure  of  his 
firm. 

3.  A  young  merchant  had  been  in  Cameroon  two  years  en- 
gaged in  expeditions  for  the  purpose  of  obtaining  rubber. 
During  these  expeditions  he  did  not  use  quinine  as  a  prophy- 
lactic, although  he  suffered  repeated  malarial  attacks.  On  a 
visit  to  another  merchant  he  was  suddenly  taken  with  a  parox- 
ysm during  which  he  distinctly  saw  an  arm  extended  from  the 
wall,  holding  a  revolver  aimed  at  him.  Seized  with  terror,  he 
fled  to  keep  from  being  murdered.  Quinine  cured  the  fever, 
but  the  delusion  of  the  arm  and  the  revolver  as  to  that  par- 
ticular time  persisted. 

4.  A  strong  young  merchant  of  healthy  family  and  without 
history  of  alcoholism  or  nervous  disorder  was  seized  three 
weeks  after  arrival  in  Cameroon  with  a  severe  estivo-autumnal 
infection.  During  the  attack  he  labored  under  the  delusion 
that  his  colleagues,  who  in  reality  nursed  him  attentively,  had 
planned  to  kill  him.  After  energetic  treatment  with  quinine 
a  complete  cure  was  effected  excepting  the  persistence  of  the 
fixed  idea  of  persecution  by  his  colleagues. 

Hysteria  is  not  a  rare  phenomenon  during  paludism.  It  is 
probably  the  result  of  anemia  in  predisposed  persons.  As  it 
may  assume  either  of  a  multitude  of  forms,  its  chief  signifi- 
cance is  from  the  viewpoint  of  diagnosis. 

A  mild  neurasthenia  is  probably  due  directly  to  malaria  in 
some  instances,  and  preexisting  neurasthenia  is  often  aggra- 
vated by  malarial  infection.  The  usual  symptoms  are  restless- 
ness, nervousness,  insomnia,  and  annoying  distinctness  of  the 
heart  beat  on  retiring. 

It  was  formerly  believed  that  intercurrent  malaria  exercised 
a  beneficial  influence  upon  epilepsy.  So  far  from  this  being 
the  case,  however,  epilepsy  is  frequently  aggravated  by  paludal 
infection. 

Violent  choreic  symptoms  are  among  the  rare  nervous  phe- 
nomena. 


248  THE   STUDY   OF  MALARIA 

The  Eye. — Injection  of  the  conjunctiva  is  not  infrequently 
associated  with  neuralgia  of  the  fifth  nerve.  True  inter- 
mittent conjunctivitis  occurs  but  rarely  if  at  all.  Both  inter- 
stitial and  dendritic  keratitis  are  occasionally  observed  with 
malaria,  though  it  is  doubtful  whether  either  form  can  be 
attributed  to  malaria.  The  same  probably  holds  true  for 
vesicular  keratitis  or  the  so-called  corneal  herpes.  In  per- 
nicious seizures  with  coma-vigil  the  eyes  are  more  or  less  ex- 
posed to  damage. 

Iritis  exists  as  a  complication  of  malaria  in  rare  instances. 
Choroiditis  occasionally  occurs  in  connection  with  retinitis. 
Optic  neuritis  is  observed  chiefly  in  cachectics.  In  the  majority 
of  cases  it  proceeds  to  atrophy. 

Retinal  hemorrhages  are  oftenest  minute  and  located  far 
forward,  hence  they  may  be  easily  overlooked.  Occasionally, 
however,  they  are  peripapillary  or  macular  and  of  large  size. 
In  the  latter  case  the  prognosis  is  more  serious.  Persistent  or 
periodic  amaurosis  without  evident  retinal  changes  is  sometimes 
seen.  The  writer  has  seen  one  case  of  hemianopia  following 
pernicious  malaria  of  the  comatose  form  which  terminated  in 
complete  restoration  of  vision.  Rarer  optic  manifestations 
occurring  in  conjunction  with  malaria  are  hemorrhage  and 
infiltration  into  the  vitreous  humor. 

The  Ear. — Otalgia,  labyrinthine  vertigo,  otitis  media,  and 
lesions  of  the  internal  ear  and  auditory  nerve  have  been  de- 
scribed as  occurring  with  malaria,  but  in  no  case  has  the  blood 
been  examined. 

The  senses  of  taste  and  smell  are  said  to  be  diminished  or 
abolished  in  rare  cases  of  malaria. 

The  Skin. — The  frequency  with  which  herpes  occurs  in 
malaria  has  already  been  mentioned.  Next  to  herpes,  urticaria 
is  the  most  frequent  cutaneous  lesion  associated  with  malaria. 
It  may  occasionally  resemble  the  eruption  of  measles.  The  pos- 
sibility of  the  eruption  being  caused  by  quinine  should  be  re- 
membered. Erythema  is  not  an.  uncommon  eruption  with 
malaria,  and  may  simulate  the  eruption  of  scarlatina.  Pruritus 
may  be  present.  Erythema  nodosum  has  occasionally  been 
observed.     Petechias  and  large  purpuric  spots  are  not  rare  in 


CLINICAL    HISTORY  249 

subjects  of  chronic  malaria  and  of  cachexia.  In  these  patients 
ulcers  and  furunculosis  may  exist  as  complications. 

The  occurrence  of  herpes  zoster  in  malaria  is  very  variable. 
In  616  cases  of  malaria  studied  by  Thayer  and  Hewetson29 
herpes  zoster  occurred  only  once,  and  this  complication  existed 
but  once  in  1,780  cases  of  malaria  reviewed  by  Anders.283 
On  the  other  hand,  Winfield334  found  malarial  parasites  in 
the  blood  of  14  out  of  25  cases  of  herpes  zoster.  The  writer 
has  recently  observed  9  cases  of  herpes  zoster.  In  3  the  blood 
examination  revealed  estivo-autumnal  parasites ;  in  2  there  was 
a  history  of  recent  malaria,  but  the  examination  of  the  blood 
was  negative,  while  in  4  there  was  no  history  of  recent  malaria 
and  the  examination  of  the  blood  was  negative. 

As  previously  mentioned,  purpura  simplex  is  not  an  uncom- 
mon occurrence  in  malaria.  Purpuric  eruptions  may  also,  but 
rarely,  be  noted  in  hemoglobinuric  fever.  But  true  purpura 
hemorrhagica  is  very  rarely  seen  in  malaria.  Eisenmann, 
Wenmarning,  and  Tchouprina,96  Bastianelli  and  Bignami,335 
Hirtz  and  Bernheim,86  Marchiafava  and  Bignami,162  and  the 
writer336  have  reported  such  cases. 

Malaria  undoubtedly  predisposes  to  the  development  of  gan- 
grene, especially  when  it  has  become  chronic  or  has  advanced 
to  cachexia.  More  than  this,  however,  cannot  be  said  of  the 
part  played  by  malaria  in  the  etiology  of  gangrene.  Gang-rene 
of  almost  every  part  of  the  surface  of  the  body  has  been  ob- 
served in  malarial  subjects.  The  gang-rene  is  more  commonly 
of  the  dry  variety.  Local  asphyxia  not  followed  by  gangrene 
occurs  also.  Raynaud's  disease,  or  symmetric  gangrene,  has 
been  thought  to  be  due  to  malaria  in  many  instances,  but  re- 
ports of  cases  in  which  the  malarial  parasite  was  present  in 
the  blood  are  still  rare. 

Other  Conditions  and  Diseases. — At  various  times  malaria 
has  been  supposed  to  predispose  to  certain  diseases.  Such  were 
typhoid  fever  and  diabetes.  It  has  also  been  thought  to  exert 
an  antagonistic  influence  toward  other  diseases,  as  tuberculosis, 
cancer,  and  influenza.  It  is  probable  that  any  predisposing 
power  on  the  part  of  malaria  to  other  diseases  is  only  indirect. 
It  is  a  priori  improbable  that  a  disease  conferring  only  relative 


250  THE   STUDY   OF   MALARIA 

immunity  toward  itself  should  immunize  against  or  antagonize 
other  diseases,  and  such  is  the  result  of  experience. 

Typhoid  Fever. — The  complication  of  typhoid  fever  with 
malaria  is  not  very  rare.  A  search  of  the  literature  reveals 
records  of  215  cases  in  which  the  presence  of  malarial  parasites 
and  the  typhoid  bacilli  or  the  Widal  reaction  conclusively 
proved  the  association. 

Typhoid  fever  is  more  frequently  complicated  with  tertian 
than  with  estivo-autumnal  malaria.  Craig337  has  reported  the 
only  case  of  simultaneous  typhoid  fever  and  quartan  malaria 
of  which  the  writer  has  any  knowledge. 

Usually  the  malarial  symptoms  arise  and  the  parasites  are 
detected  during  convalescence  from  the  typhoid  fever,  though 
they  may  be  present  during  the  course  of  the  latter.  When 
the  onset  of  the  malaria  precedes  that  of  the  typhoid  fever  the 
malarial  parasites  often  disappear  from  the  peripheral  circu- 
lation upon  the  advent  of  the  typhoid  fever,  sometimes  re- 
appearing and  producing  symptoms  during  the  convalescence 
from  typhoid.  This  is  analagous  to  the  result  of  inoculating 
a  given  variety  of  malarial  parasites  into  a  malarial  patient 
harboring  a  different  form,  the  older  infection  usually  sur- 
rendering to  the  fresh.  Malaria  occurring  at  the  height  of 
typhoid  fever  may  or  may  not  modify  the  course  of  the 
latter.  The  mortality  of  the  complication  of  these  two  fevers 
is  higher  than  that  of  uncomplicated  typhoid. 

The  term  "typhomalarial  fever,"  if  used  at  all,  should  be 
restricted  to  those  cases  in  which  exact  methods  of  diagnosis 
prove  it  applicable.  However,  the  combination  of  typhoid  and 
malarial  fevers  is  no  more  entitled,  either  by  virtue  of  intimacy 
or  frequency,  to  a  hyphenated  appellation  than  is  tuberculosis 
or  gonorrhea  in  association  with  malaria.  It  was  formerly 
believed  that  a  mysterious  fusion  of  both  diseases  produced  a 
hybrid  pathologic  entity.  It  is  now  definitely  known  that  this 
is  not  the  case.  Such  a  diagnosis  is  ordinarily  a  compromise 
based  on  a  lack  of  frankness  to  acknowledge  inability  to  diag- 
nose certain  cases  of  fever  in  the  earliest  stages,  and  is  not  only 
loose  and  unscientific,  but  is,  in  many  instances,  actually  harm- 
ful, as  it  often  leads  to  the  abuse  of  purgatives  and  quinine. 


CLINICAL    HISTORY  25 1 

There  is  no  question  but  that  nearly  all  of  the  so-called  "typho- 
malaria"  is  pure  typhoid  fever. 

Diabetes. — In  spite  of  the  great  frequency  with  which  Bur- 
del86  claims  to  have  found  glycosuria  complicating  malaria  (92 
times  in  382  cases  of  malaria),  it  must  be  considered  a  rare 
complication.  Ziemann,48  Wittrock,49  and  Marchiafava  and 
Bignami22  observed  1  case  each,  and  Hemmeter314  mentions 
records  of  198  urinalyses  in  cases  of  malaria  gathered  from 
various  hospitals,  only  2  of  which  indicated  diabetes  mellitus. 
The  writer  recalls  the  case  of  a  diabetic,  passing  more  than  5 
per  cent,  of  sugar,  who  was  attacked  with  estivo-autumnal 
malaria.  The  latter  ran  an  uneventful  course  and  seemed  to 
have  no  effect  on  the  sugar  excretion.  The  patient  died  sev- 
eral months  later  of  bronchitis. 

Polyuria  in  malarial  subjects  has  already  been  mentioned. 
Tuberculosis.— -In  the  South,  where  tuberculosis  is  very 
prevalent  in  the  negro  race,  the  negro  death  rate  from  tuber- 
culosis ranging  from  100  to  150  per  cent,  higher  than  in  the 
white  race,  tuberculosis  and  malaria  not  infrequently  concur, 
especially  in  the  colored  race.  Malarial  cachexia  predisposes 
to  tuberculosis  only  in  a  slight  measure,  if  at  all.  The  negro, 
who  is  less  often  the  subject  of  cachexia  than  the  white,  more 
often  shows  the  combination  of  malaria  and  tuberculosis.  The 
malaria  may  prove  rapidly  fatal,  both  diseases  may  be  un- 
modified in  their  progress,  or  the  tuberculosis  may  assume  a 
more  rapid  course.  The  old  idea  that  the  two  diseases  are 
antagonistic  is  disproved  not  only  by  their  not  uncommon 
occurrence  in  the  same  individual,  but  Kelsch  and  Kiener17* 
have  even  found,  in  several  autopsies,  evidence  of  both  dis- 
eases in  the  same  organs,  as  the  liver  and  spleen. 

Influenza.— Anders337  believes  that  there  exists  a  decided 
antagonism  between  malaria  and  influenza.  Simms  and  War- 
wick,85 however,  mention  simultaneous  epidemics  of  malaria 
and  influenza  in  Alabama,  when,  "of  those  infected  with  mala- 
ria, 60  per  cent,  were  brought  down  with  this  disease,  and  it 
was  much  more  severe  than  in  those  who  were  not  infected.'" 

Cancer.— Based  on  the  supposition  that  cancer  is  not  so  fre- 
quent in  tropic  latitudes,  and  on  the  report  of  Krzowitz,  in 


252  THE   STUDY   OF   MALARIA 

1776,  of  a  case  of  cancer  of  the  breast  healing  after  an  attack 
of  double  tertian  malaria,  Loffler338  assumed  an  antagonism  be- 
tween the  two  diseases,  and  proposed,  as  a  therapeutic  measure, 
the  inoculation  with  malaria  of  cancerous  patients.  A  few 
experiments  and  numerous  reports  of  cancer  among  tropic 
people  and  malarial  subjects  have  shown  the  absolute  useless- 
ness  of  such  a  procedure.  On  the  other  hand,  it  is  believed 
that  malaria  of  long  standing  predisposes  to  cancer  of  the  liver. 

Smallpox  is  an  infrequent  complication  of  malaria.  La- 
veran1  observed  several  such  cases  in  Constantine.  The  mala- 
rial parasites  usually  disappeared  from  the  blood  with  the 
onset  of  the  smallpox  where  the  onset  of  the  latter  succeeded 
that  of  the  former.  The  mortality  of  these  cases  was  unusu- 
ally high.     Pyemic  foci  and  hemorrhages  were  observed. 

Syphilis  is  a  common  complication  of  paludism.  Under 
these  circumstances  syphilis  is  more  rapid  in  its  course  and  is 
rebellious  to  treatment  in  proportion  to  the  chronicity  of  the 
malarial  infection.  In  malarial  cachectics  antisyphilitic  treat- 
ment is  sometimes  all  but  impotent.  Syphilitic  buboes  are 
more  apt  to  suppurate  and  become  ugly  indolent  ulcers.  Mala- 
rial invasion  may  arouse  latent  syphilis. 

Vincent159  is  of  the  opinion  that  the  colon  bacillus  often  as- 
sumes pathogenic  importance  in  malarial  infections,  and  he 
terms  the  result  "coli-malarial  fever."  The  patients  are  pro- 
foundly malarial;  they  present  a  fever  of  continued  type  and 
typhoid  phenomena,  subdelirium,  coma,  diarrhea,  etc.  At 
autopsy  there  are  no  intestinal  lesions  save  a  few  psorenteric 
plagues.  Some  show  extensive  foci  of  necrosis  in  the  spleen 
or  small  miliary  abscesses;  others  suppurating  points  in  the 
kidneys.  Siderosis  is  found  in  the  spleen  and  liver.  Bacterio- 
logic  examination  shows  a  generalized  infection  with  the  bacil- 
lus coli  commumis.  The  eccentric  and  iconoclastic  Legrain255 
believes  that  the  role  of  the  colon  bacillus  in  exotic  pathology  is 
immense. 

In  the  present  state  of  our  knowledge  it  is  impossible  to  de- 
termine the  part  played  by  the  colon  bacillus  in  the  fevers  of 
warm  countries.  In  subtropic  and  tropic  climates,  with  an 
exuberant  flora,  it  is  theoretically  not  impossible  that  the  colon 


CLINICAL   HISTORY  253 

bacillus  may  acquire  an  unusual  degree  of  virulence  and  give 
rise  to  auto-intoxications.  Every  Southern  physician  is  familiar 
with  ephemeral  fevers,  usually  attributed  to  "biliousness," 
which  disappear  after  the  administration  of  an  antiseptic  purge, 

as  calomel. 

The  association  of  scorbutus  and  malaria  was  formerly 
frequently  encountered  in  military  practice  during  campaigns. 
It  is  now  rarely  seen,  especially  in  civil  practice. 

Valenti339  and  Lioubenetzy340  have  each  observed  in  malarial 
subjects  symptoms  recalling  Addison's  disease. 

Malaria  in  Children.— In  older  children  there  is  nothing 
unusual  in  the  malarial  attacks.  In  infants  and  young  children 
there  are  several  points  which  deserve  a  brief  consideration. 

The  type  of  fever  is  most  often  quotidian,  sometimes  tertian 
or  double  quotidian,  rarely  quartan.  The  paroxysm  occurs 
more  often  during  the  night  than  is  the  case  with  the  adult, 
the  fever  being  often  detected  for  the  first  time  in  the  morn- 
ing- 

The  first  stage  is  rarely  typic,  the  rigor  being  replaced  by 

coldness  of  the  extremities,  pallor,  slight  cyanosis,  especially 
of  the  lips  and  nails;  vomiting,  drowsiness,  and  sometimes 
convulsions.  During  the  second  stage  the  fever  is  ordinarily 
higher  than  in  the  adult.  Gastrointestinal  symptoms,  particu- 
larly vomiting  and  diarrhea,  are  common.  Thirst  is  usually 
intense.  The  most  common  complaints  are  pain  in  the  head 
and  epigastric  region.  Enlargement  of  the  spleen  is  more 
constant  than  in  the  adult.  Torticollis  and  erythema  may 
be  noted.  Atypic  forms  and  dangerous  symptoms,  especially 
on  the  part  of  the  nervous  and  gastro-intestinal  systems,  are 
frequent.     Edema,  ascites,  and  purpura  are  not  uncommon. 

Malaria  in  the  Negro.— The  relative  immunity  of  the  negro 
race  to  the  severe  manifestations  of  malaria  and  to  hemoglo- 
binuria fever  has  been  mentioned.  It  remains  only  to  cite  a 
few  clinic  features  of  malaria  in  this  race. 

Estivo-autumnal  malaria  is  much  more  common  in  the  col- 
ored race  than  are  tertian  and  quartan.  The  paroxysms  usu- 
ally occur  during  the  day,  but  night  paroxysms  are  more  com- 
mon than  in  the  white  race.     A  well-defined  and  severe  cold 


254  THE   STUDY   OF  MALARIA 

stage,  while  not  at  all  rare  in  the  negro,  is  more  frequently- 
lacking  than  in  the  accesses  in  the  white.  Herpes  is  relatively- 
rarer  in  the  black.  Uncontrollable  vomiting  is  not  nearly  so 
frequent  in  the  colored  race  as  in  the  white.  Marked  splenic 
enlargement  is  much  less  common  in  the  negro,  palpable  spleens 
in  the  adult  negro  being  infrequent.  The  extremely  low  hemo- 
globin percentages,  which  are  not  rare  in  chronic  malaria  and 
cachexia  of  white  persons,  are  far  less  frequently  observed  in 
the  negro.  As  previously  stated,  cachexia  is  decidedly  more 
prevalent  in  the  white  race.  Malarial  parasites  are  altogether 
absent  from  the  peripheral  blood  of  negroes  in  a  larger  per 
cent,  of  cases  than  they  are  wanting  in  white  patients.  When 
present  they  are  more  frequently  scanty.  On  the  other  hand, 
the  negro  may  harbor  large  numbers  of  parasites  without 
manifesting  any  symptoms.  Pulmonary  complications,  bron- 
chitis, pneumonia,  and  tuberculosis  are  more  frequent  in  the 
negro.  Nephritis  is  another  complication  of  which  this  is 
true.  Hysteria  and  other  neuroses  are  probably  more  common 
in  the  colored  female.  The  abuse  of  snuff,  which  is  under- 
mining the  nervous  stability  of  the  majority  of  adult  negro 
females  in  the  South,  may  help  to  account  for  this.  There 
is  less  tendency  to  abort  during  pregnancy  complicated  with 
malaria  in  the  colored  female  than  in  the  white.  Spontaneous 
cure  after  only  one  or  two  paroxysms  is  a  common  termina- 
tion of  malaria  in  the  negro.  Every  physician  practising 
among  this  race  is  familiar  with  the  frequency  with  which 
their  attacks  of  malaria  end  after  a  "round"  of  purgative  and 
a  potion  of  "tea"  of  some  sort.  The  grave  forms  of  malaria 
occurring  less  often,  the  mortality  is  consequently  lower  in 
the  negro  race. 

The  Surgical  Aspect  of  Malaria. — Trauma  may  aggravate 
active  malaria  or  arouse  it  from  latency.  On  the  other  hand, 
malarial  infection  reacts  upon  wounds.  Slight  wounds,  such 
as  that  caused  by  the  extraction  of  a  tooth,  may  in  cachectics 
give  rise  to  excessive  hemorrhage.  Fractures  heal  more  slowly 
in  malarial  subjects.  The  writer  has  more  than  once  observed 
suppuration,  ulceration,  and  sloughing  in  the  wounds,  aseptic- 
ally  treated,  of  malarial  persons,  especially  sawmill  employes 


CLINICAL    HISTORY  255 

and  timbermen.  If  surgical  measures  are  contemplated  in 
patients  with  a  history  of  recent  malaria  the  blood  should 
be  examined  carefully  for  evidences  of  malaria,  which,  if 
present,  might  figure  in  the  result. 

With  reference  to  the  surgical  relations  of  malaria  the  fol- 
lowing conclusions  are  justifiable: 

1.  In  subjects  of  active  malaria,  wounds  are  apt  to  aggravate 
the  malaria. 

2.  In  subjects  of  latent  malaria,  trauma  is  apt  to  excite  the 
latter  into  activity. 

3.  Chronic  malaria  and  cachexia  may  complicate  wounds 
by  increasing  the  tendency  to  hemorrhage,  suppuration, 
sloughing,  indolence,  or  even  gangrene. 

4.  The  mere  presence  of  parasites  in  the  blood  without  pro- 
ducing symptoms  (absolute  latency)  is  no  bar  to  operation,  as 
the  specific  treatment  may  be  pursued  with  the  surgical. 

5.  In  badly  debilitated  subjects  of  chronic  malaria  and  of 
cachexia  only  operations  of  necessity  should  be  undertaken, 
and  then  quinine  and  tonics  should  form  part  of  the  after- 
treatment. 


CHAPTER  VI 

DIAGNOSIS 

Malaria  is  the  scapegoat  of  tropic  pathology  and  quinine 
the  high  priest. 

Too  often  is  the  mocking  equation  of  Legrain, 

Fever=zMalaria=^  Quinine, 

employed  to  solve  the  diagnostic  problems  of  the  fevers  of 
warm  climates. 

There  are  three  sources  from  which  information  may  be 
drawn  to  make  a  diagnosis  of  malaria;  first,  from  the  symp- 
toms; second,  from  the  examination  of  the  blood;  and  third, 
from  the  effect  of  quinine  upon  the  symptoms. 

I.  Of  the  clinical  history  the  most  important  feature  to  be 
considered  is  periodicity.  Tertian  and  quartan  periodicity  are 
pathognomonic  of  malaria.  Sometimes  the  statements  of 
patients  cannot  be  relied  on  with  respect  to  the  course  of  their 
ailments,  and  tertian  and  quartan  periodicity  must  be  abso- 
lutely determined  to  be  of  diagnostic  value.  By  this  is  not 
meant  that  the  disease  must  be  observed  by  the  physician  un- 
treated until  such  periodicity  is  established,  but  that  value  of 
this  symptom  is  in  proportion  to  the  reliability  of  the  source 
from  which  the  history  is  derived.  Unfortunately  this  perio- 
dicity is  of  little  value  in  estivo-autumnal  infections,  in  which 
the  importance  and  difficulty  of  diagnosis  are  greater. 

Quotidian  periodicity  is  not  only  worthless,  but  actually 
misleading  in  the  diagnosis  of  malaria.  It  is  especially  in 
septic  conditions  that  mistakes  are  oftenest  made,  where  not 
infrequently  is  the  rhythmic  quotidian  succession  of  chill, 
fever,  and  sweat  mistaken  for  the  metric  march  of  malaria. 
A  noted  clinician  has  said  that  he  has  rarely  seen  a  case  of 
abscess  of  the  liver  that  had  not  been  drenched  with  quinine, 
and  his  experience  is  not  unique  in  this  respect.     Malaria  is 

256 


DIAGNOSIS  257 

by  no  means  the  only  condition  accompanied  with  cold,  hot, 
and  sweating  stages,  and  one  or  two  of  these  stages  are  some- 
times wanting  in  malaria.  Abscess  of  the  liver,  gall-stone 
disease,  tuberculosis,  and  numerous  other  diseases  may  exhibit 
temperature  charts  closely  resembling  that  of  malaria. 

It  should  be  borne  in  mind,  however,  that  quotidian  fever 
in  malaria  may  show  tertian  or  quartan  periodicity.  Thus  in 
double  tertian  the  paroxysms  of  the  first  and  third  days  may 
occur  at  a  certain  hour  in  the  morning,  and  those  of  the  second 
and  fourth  days  at  a  certain  hour  in  the  afternoon.  Tertian 
periodicity  in  quotidian  fever  is  valuable  from  a  diagnostic 
view  in  proportion  as  the  paroxysms  on  successive  days  are 
separated  from  a  given  hour  and  those  on  alternate  days 
approach  a  given  hour,  or,  in  other  words,  as  the  alternate 
paroxysms  approach  a  forty-eight-hour  interval,  while  the 
accesses  on  successive  days  are  distant,  by  more  or  less,  from 
a  twenty-four-hour  interval.  Quartan  periodicity  in  quotidian 
fever  rarely  comes  into  consideration  in  diagnosis  on  account 
of  the  relative  rarity  of  the  triple  quartan  infections,  the 
promptness  with  which  the  microscope  decides  the  matter,  and 
the  more  frequent  tendency  of  one  or  two  of  the  three  groups 
of  parasites  to  sporulate  approximately  twenty- four  hours  after 
the  last  preceding.  The  course  of  a  double  quartan  infection, 
two  successive  fever  days  followed  by  a  fever-free  day,  is 
pathognomonic. 

It  may  be  stated  as  a  general  rule  that  tertian  and  quartan 
periodicity  are  of  importance  in  diagnosis  in  proportion  to  the 
length  of  the  series  of  paroxysms,  since  it  is  not  impossible 
that  fever  on  only  two  days  separated  by  one  or  two  days  of 
apyrexia  might  occur  adventitiously  from  causes  other  than 
malaria.  It  is  the  repetition  of  this  succession  that  indicates 
malaria,  hence  the  periodicity  must  be  perfectly  established. 

The  characteristic  curve  of  tertian  estivo-autumnal  fever  is 
probably  pathognomonic,  but  can  be  obtained  in  only  a  small 
proportion  of  cases  in  private  practice.  The  clinical  course  of 
estivo-autumnal  infections  is  of  much  less  value  in  diagnosis 
than  that  of  tertian  and  quartan. 

The  value  of  enlargement  of  the  spleen  in  the  diagnosis 

17 


258  THE   STUDY   OF  MALARIA 

of  malaria  has  certainly  been  overrated.  In  regions  where 
there  is  little  malaria,  the  endemic  index  being  low,  it  is  proba- 
bly a  point  of  some  worth.  On  the  other  hand,  in  malarial 
regions  of  high  index  endemicus  it  is  worth  much  less.  It  is 
almost  valueless  in  malaria  occurring  in  negroes,  as  it  is  infre- 
quently sufficiently  enlarged  to  be  palpable,  and  unless  palpable 
is  of  no  diagnostic  value.  Physicians  in  malarial  regions  are 
all  familiar  with  the  frequency  with  which  the  enlarged  spleen 
of  the  subject  of  chronic  malaria  or  cachexia  complicates  other 
diseases.  If  the  physician  is  sufficiently  familiar  with  the 
patient  to  know  that  the  splenic  enlargement  is  acute,  it  be- 
comes a  matter  of  some  importance,  but  the  statement  of  the 
patient  as  to  the  former  condition  of  the  organ,  even  when  the 
latter  is  immense,  is  not  always  to  be  relied  upon. 

Herpes  when  present  is  an  aid  to  diagnosis.  The  only  dis- 
ease in  which  it  occurs  with  anything  like  the  frequency  it 
does  in  malaria  is  pneumonia. 

2.  The  microscopic  examination  of  the  blood  for  the  diag- 
nosis of  malaria  determines  the  presence  or  absence  of  para- 
sites, pigment,  and  leukocytosis,  and  the  numeric  relation  of 
the  leukocytes. 

Before  attempting  the  diagnosis  of  malaria  by  the  micro- 
scopic examination  of  the  blood  the  beginner  must  become 
thoroughly  familiar  with  the  appearance  of  normal  blood  and 
with  the  technic  of  examination,  and  he  should  not  rely  too 
much  upon  the  result  of  an  examination  until  he  has  had  con- 
siderable experience  with  malarial  blood. 

While  Laveran  made  his  discovery  with  a  one-sixth-inch 
lens,  only  a  one-twelfth-inch  oil  immersion  lens,  with  appro- 
priate condenser  and  diaphragm,  should  be  employed,  and  the 
mechanic  stage  greatly  facilitates  the  work.  Thin  slides  and 
cover-glasses  should  be  used. 

While  stained  films  of  the  blood  have  a  wider  field  of  use- 
fulness to  the  general  practitioner  than  preparations  of  the 
unstained  blood,  he  should  become  familiar  with  the  technic 
of  each. 

When  about  to  obtain  blood  to  be  examined,  fresh  and 
unstained,  several  slides  and  cover-glasses,  having  been  washed 


Fig.  67. — Making  the  puncture. 


Fig.  69. — Obtaining  the  blood  between  slide  and  cover-glass. 


DIAGNOSIS  259 

thoroughly  with  soap  and  water,  then  with  alcohol,  should  be 
rubbed  thoroughly  with  an  old,  clean  handkerchief  and  gently 
warmed.  While  the  blood  may  be  obtained  elsewhere,  the  lobe 
of  the  ear  has  advantages  over  other  locations ;  it  is  less  sensi- 
tive, it  being  possible  to  obtain  blood  from  sleeping  children 
without  awakening  them;  the  instrument  and  the  blood  may 
be  kept  from  the  view  of  the  patient,  an  advantage  when  deal- 
ing with  children  and  nervous  persons.  More  blood  is  easily 
obtained  if  desired  to  make  a  hemoglobin  estimation,  blood 
count,  or  Widal  test.  The  lobe  of  the  ear  should  be  cleaned 
with  soap  and  water,  then  with  alcohol,  and  should  be  dried 
thoroughly.  It  is  then  grasped  between  the  thumb  and  fore- 
finger, the  latter  uppermost.  The  puncture  is  made  preferably 
with  a  large  straight  Hagedorn  needle  (Fig.  67),  and  should 
be  made  quickly  to  the  depth  of  about  one-eighth  inch.  The 
first  one  or  two  drops  should  be  wiped  away  and  one  chosen 
which  is  not  too  large. 

The  cover-glass,  held  by  diagonal  corners  between  the  thumb 
and  forefinger,  or,  better,  by  means  of  forceps  applied  to  the 
summit  of  the  blood-drop  and  laid  face  down  upon  the  slide. 
Care  must  be  taken  to  touch  only  the  top  of  the  drop  and  not 
the  skin,  otherwise  the  blood  smeared  upon  the  cover-glass 
will  have  begun  to  coagulate  around  the  margin  and  will  not 
spread  freely.  It  is  a  common  mistake  to  take  too  large  a 
drop  of  blood,  and  if  the  blood  extends  to  the  edges  of  the 
cover-glass  and  the  center  of  the  film  has  a  ground-glass  ap- 
pearance it  should  be  discarded.  If  the  blood  does  not  spread 
freely  and  evenly  it  is  better  not  to  use  pressure,  but  the  cover- 
glass  may  be  gently  pushed  by  the  needle  applied  to  its  edge. 
Several  preparations  should  be  made  to  insure  a  good  one, 
and  each  time  the  ear  should  be  wiped  free  of  blood  and  a 
fresh  drop  taken.  A  rim  of  vaseline  around  the  edges  of  the 
cover-glass  will  preserve  the  specimen  longer. 

As  simple  as  this  seems  it  requires  considerable  practice  to 
obtain  films  in  which  the  red  cells  lie  side  by  side  and  not  in 
rouleaux. 

Hayem's  method  gives  better  results  in  the  hands  of  the 
amateur.     A  square  cover-glass  is  placed  upon  a  slide  in  such 


260  THE   STUDY   OF   MALARIA 

a  manner  that  one  edge  of  the  cover-glass  coincides  exactly 
with  the  edge  of  the  slide  near  its  middle.  Held  rather  firmly 
in  this  position  by  the  thumb  and  forefinger,  the  coapted 
edges  are  applied  to  the  blood-drop  when  the  blood  spreads 
evenly  between  the  slide  and  cover-glass  (Fig.  69).  When 
the  blood  has  almost  reached  the  opposite  edge  of  the  cover- 
glass  enough  blood  has  been  obtained.  Two  cover-glasses 
may  be  used  instead  of  a  slide  and  cover-glass,  and  when  ready 
to  be  examined  one  of  the  cover-glasses  cemented  at  the  corner 
or  edge  to  a  slide  by  means  of  Canada  balsam. 

The  advantages  of  dried  films  over  fresh  preparations  of 
blood  are  several.  Cleanliness  of  the  part  from  which  the 
blood  is  taken  and  the  size  of  the  drop  are  not  so  important. 
This  advantage  is  appreciated  by  the  practitioner  who  often 
has  to  make  the  preparation  in  the  remote  corner  of  an  ill- 
lighted  cabin.  The  slides  may  be  laid  aside  and  examined  at 
leisure,  weeks  or  even  months  later.  The  differential  leukocyte 
count  can  be  made  on  the  same  slide. 

It  is  not  necessary  that  the  region  from  which  the  blood  is 
taken  should  be  perfectly  clean,  but  if  perspiration  is  present 
this  should  be  wiped  off.  The  ear  is  held  and  the  puncture 
made  as  described  for  wet  films.  The  slide,  held  in  the  right 
hand,  is  rested  against  the  thumb  and  forefinger  holding  the 
lobe  of  the  ear,  and  gradually  lowered  until  it  receives  the  drop 
of  blood  near  one  end. 

The  smear  may  be  made  by  either  one  of  three  useful  meth- 
ods. The  simplest  is  to  hold  the  slide  in  the  left  hand  and  with 
the  right  lay  the  shaft  of  the  needle  across  the  drop  of  blood 
(Fig.  70).  After  waiting  a  few  moments  for  the  blood  to 
spread  out  between  the  needle  and  the  slide,  the  needle  is 
evenly  and  gradually  drawn  to  the  opposite  end  of  the  slide. 
Drying  the  film  by  rapidly  waving  it  in  the  air  preserves  the 
form  of  the  red  cells. 

Instead  of  the  needle  the  end  of  another  slide  may  be  applied 
to  the  drop  of  blood  (Fig.  71)  so  that  the  two  slides  meet  at 
an  angle  of  about  45  degrees ;  after  waiting  for  the  blood  to 
spread  along  the  edge  of  the  slide,  the  upper  slide  is  then 


Fig.   70. — Making  the  spread. 


Fig.  71. — Using  another  slide  to  spread  the  blood. 


Fig.   12. — The  cigarette-paper  method. 


DIAGNOSIS  26l 

drawn  to  the  opposite  end  of  the  lower,  and  the  film  dried  by- 
waving. 

Cigarette  paper  may  be  used  as  follows :  Strips  about  three- 
fourths  of  an  inch  wide  are  cut  perpendicularly  to  the  ribs  of 
the  paper;  the  end  of  one  of  these  strips,  the  original  machine- 
cut  edge,  is  applied  to  the  blood-drop  near  the  end  of  the  slide, 
and  after  a  few  moments  drawn  to  the  opposite  end  of  the 
slide.  Other  paper  may  be  employed  if  cigarette  paper  is  not 
available,  but  does  not  answer  so  well  (Fig.  72). 

If  flies  gain  access  to  unstained  films  they  will  rapidly  devour 
the  blood. 

Many  staining  methods  have  been  proposed  to  demonstrate 
the  malarial  parasite  in  the  blood.  A  common  mistake  for 
the  student  to  make  is  to  attribute  bad  results  to  the  stain,  and 
to  discard  a  method  before  he  has  become  familiar  with  it.  In 
no  branch  of  pathology  is  attention  to  minute  details  of  technic 
of  greater  influence  upon  results,  and  a  method  should  be 
thoroughly  mastered  before  passing  judgment  upon  it. 

Malarial  parasites  take  basic  stains,  of  which  methylene-blue 
is  most  frequently  employed. 

The  parent  of  our  modern  stains  for  the  malarial  parasite 
is  that  of  Romanowsky.  The  films  are  made  upon  cover- 
glasses  by  obtaining  a  drop  of  blood  upon  the  center  of  one 
cover-glass  and  laying  another  diagonally  across  it.  As  soon 
as  the  blood  has  spread  the  cover-glasses  are  drawn  apart  in 
the  same  plane,  not  lifted.  When  dry  the  films  are  fixed  by 
immersion  in  absolute  alcohol  for  ten  minutes,  or  in  equal  parts 
of  absolute  alcohol  and  ether  for  thirty  minutes,  or  by  heating 
in  an  oven  to  150°  C,  when  they  are  removed  and  allowed  to 
cool. 

The  Romanowsky  method  necessitates  two  solutions,  a  satu- 
rated watery  solution  of  methylene-blue,  and  a  1  per  cent, 
watery  solution  of  eosin.  Old  solutions  of  methylene-blue  give 
better  results  than  recent.  The  staining  solution  is  mixed 
immediately  before  use  as  follows : 

Methylene-blue  solution,  2  parts; 
Eosin  solution,  4  to  5  parts. 

A  precipitate  will  form,  which  should  not  be  filtered  out, 


262  THE  STUDY   OF  MALARIA 

though  the  methylene-blue  solution  may  be  filtered  before  mix- 
ing with  the  eosin  if  desired.  The  mixture  is  poured  into  a 
watch-glass  and  the  films  floated  blood  side  down  upon  its 
surface  for  two  or  three  hours.  They  are  then  washed  in 
water,  dried,  and  mounted. 

Ewing130  describes  Nocht's  modification  of  Romanowsky's 
method  as  follows : 

1.  To  1  ounce  of  polychrome  methylene-blue  (Grubler)  add 
5  drops  of  3  per  cent,  solution  of  acetic  acid  (U.  S.  P.  33  per 
cent. ) . 

2.  Make  a  saturated  ( 1  per  cent. )  water  solution  of  methyl- 
ene-blue, preferably  Ehrlich's  rect.  (Grubler),  or  Koch's,  dis- 
solving the  dye  by  gentle  heat.  This  solution  improves  with 
age,  and  should  be  at  least  one  week  old. 

3.  Make  a  1  per  cent,  solution  in  water  of  (Grubler's)  aque- 
ous eosin. 

The  mixture  is  prepared  as  follows : 

To  10  cc.  of  water  add  4  drops  of  the  eosin  solution,  6  drops 
of  neutralized  polychrome  blue,  and  2  drops  of  1  per  cent, 
methylene-blue,  mixing  well.  The  specimens  fixed  in  alcohol 
or  by  heat  are  immersed  for  two  hours,  specimen  side  down, 
and  will  not  overstain  in  twenty-four  hours.  The  density  of 
the  blue  stain  may  be  varied  to  suit  individual  preferences.  The 
above  proportions  need  not  be  rigidly  followed,  but  the  poly- 
chrome solution  should  be  accurately  neutralized. 

Leishman's  solution  combines  the  fixing  and  staining  proper- 
ties into  one  solution,  the  whole  process  requiring  only  a  few 
minutes.  Its  manufacture  is,  however,  rather  tedious.  Two 
solutions  are  necessary.  The  first  consists  of  Grubler's 
methylene-blue,  1  part;  sodium  carbonate,  0.5  part;  distilled 
water,  100  parts.  This  solution  is  rendered  polychrome  by 
heating  to  65°  C.  for  twelve  hours,  then  exposing  to  room  tem- 
perature for  a  week  or  ten  days.  The  other  is  a  1  :  1000 
watery  solution  of  Grubler's  eosin.  Equal  parts  of  these  solu- 
tions are  mixed  and  allowed  to  stand  for  six  to  twelve  hours, 
stirring  occasionally.  The  mixture  is  then  filtered  and  the 
filtrate  thoroughly  washed  with  distilled  water  and  dried.  The 
dried  filtrate  is  the  stain,  and  0.15  gram  is  dissolved  in  100  cc. 


Fig.   73. — Making  films  upon  cover-glasses. 


Fig.  74. — If  the   forceps  are  applied   to   the   center  of  the   slide   the   stain  will 

not  run  off. 


DIAGNOSIS  263 

pure  methyl  alcohol  and  kept  tightly  stoppered.  For  staining 
a  few  drops  are  placed  upon  the  dried,  unfixed  blood  film  and 
allowed  to  stand  one-half  to  one  minute,  when  about  twice 
the  quantity  of  water  is  added,  or  until  the  precipitated  stain 
is  seen  floating  upon  the  surface.  After  five  minutes  the 
slide  is  washed  in  water  for  about  a  minute  and  dried  between 
filter  paper. 

The  most  easily  prepared  of  the  combined  fixing  and  stain- 
ing solutions,  and  giving  results  as  satisfactory  as  any, 
Wright's,  is  described  by  the  originator  as  follows  :341 

"This  staining  fluid  is  an  improvement  on  one  devised  by 
W.  B.  Leishman  because  it  requires  only  a  few  hours  and  an 
ordinary  steam  sterilizer  for  its  preparation,  while  Leishman's 
required  at  least  eleven  days  and  the  employment  of  a  thermo- 
stat regulated  at  65°  C.  Leishman  deserves  great  credit  for 
originating  a  method  of  staining  blood  films  and  malarial  para- 
sites which  combines  the  important  'Romanowsky'  staining 
with  the  great  advantages  of  the  methyl-alcohol  method  of 
Jenner.  Wright's  stain  is  applied  in  the  same  manner  and 
gives  the  same  results. 

"It  is  preferred  to  Ehrlich's  stain  because  it  does  not  require 
the  difficult  and  uncertain  fixation  of  the  blood  film  by  heat 
and  because  it  gives  constantly  satisfactory  results  even  in  the 
hands  of  inexperienced  workers. 

"This  stain  makes  visible  in  the  blood  smear  not  only  all  that 
the  Ehrlich  stain  does,  but  more,  for  it  gives  the  differential 
Romanowsky  staining  to  mast-cells,  blood-plates,  certain  de- 
generate products  in  the  red  corpuscles,  and  to  malarial  and 
other  protozoan  parasites,  thus  accomplishing  at  one  and  the 
same  time  all  that  which  usually  requires  the  employment  of 
several  special  staining  methods  separately  applied. 

"It  is  prepared  as  follows : 

"Dissolve  0.5  gm.  of  sodium  bicarbonate  in  100  cc.  of  dis- 
tilled water,  add  1  gm.  of  methylene-blue  (Grubler).  Any  of 
the  methylene-blues  of  Grubler,  known  as  'BX,'  'Koch's,'  or 
'Ehrlich's  rectified,'  may  be  used.  It  seems  to  be  important 
that  the  bicarbonate  of  soda  be  all  dissolved  before  adding  the 
methylene-blue. 


264  THE   STUDY   OF   MALARIA 

"The  mixture  is  next  to  be  steamed  in  an  ordinary  steam 
sterilizer  at  ioo°  C.  for  one  hour,  counting  the  time  after 
'steam  is  up.'  The  heating  should  not  be  done  in  a  pressure 
sterilizer,  or  in  a  water-bath,  or  in  any  other  way  than  as 
stated.  This  steaming  of  the  alkaline  solution  of  methylene- 
blue  effects  certain  changes  in  the  methylene-blue  whereby  a 
polychromatic  property  is  given  to  it,  so  that  the  compound 
with  eosin,  which  is  later  to  be  formed  with  it,  has  the  prop- 
erty not  only  of  differentially  staining  the  chromatin  of  the 
malarial  parasite,  but  also  of  differentiating  and  bringing  out 
more  sharply  the  nuclei  and  granules  of  the  white  blood  cor- 
puscles. 

"When  the  steaming  is  completed  the  mixture  is  removed 
from  the  sterilizer  and  allowed  to  cool,  the  flask  being  placed 
in  cold  water  if  desired.  When  it  is  cold,  without  filtering, 
pour  it  into  a  large  dish  or  flask  and  add  to  it,  stirring  or  shak- 
ing meanwhile,  a  sufficient  quantity  of  a  1 :  1000  solution  of 
eosin  (Grubler,  yellowish,  soluble  in  water)  until  the  mixture, 
losing  its  blue  color,  becomes  purple  in  color  and  a  scum  with 
yellowish  metallic  lustre  forms  on  the  surface,  while  on  close 
inspection  a  finely  granular  black  precipitate  appears  in  suspen- 
sion. This  will  require  about  500  cc.  of  the  eosin  solution  for 
100  cc.  of  the  alkaline  methylene-blue  solution.  These  are 
quantities  which  are  convenient  and  suitable  to  employ. 

"The  precipitate  is  collected  on  a  filter  and,  without  washing, 
is  allowed  to  dry  thereon.  When  thoroughly  dry  dissolve  this 
precipitate  in  pure  methyl-alcohol  in  the  proportion  of  0.5  gm. 
to  100  cc.  of  alcohol.  This  alcoholic  solution  is  the  staining 
fluid.  It  is  not  necessary  to  filter  it.  It  will  keep  indefinitely, 
as  will  also  the  dry  precipitate.  Precautions  should  be  taken 
to  keep  the  alcohol  from  evaporating,  for  thus  the  solution 
may  become  too  saturated  and  precipitates  may  form  on  the 
blood  film  in  the  process  of  staining.  If  the  staining  fluid 
deposits  such  precipitates  it  should  be  filtered  and  a  small  quan- 
tity of  methyl-alcohol  added  to  it.  . 

"The  films  of  blood,  which  should  be  spread  thinly,  are  al- 
lowed to  dry  in  the  air.  When  dry,  as  much  of  the  staining 
fluid  is  poured  upon  the  film  as  the  cover-glass  will  readily 


DIAGNOSIS  265 

hold  without  draining  off.  Allow  the  staining  fluid  to  remain 
in  contact  with  the  film  for  one  minute.  This  chiefly  serves 
the  purpose  of  fixing  the  blood  corpuscles.  The  cover-glass 
is  most  conveniently  manipulated  by  means  of  cover-glass 
forceps. 

"Next  add  to  the  staining  fluid  on  the  cover-glass  distilled 
water,  drop  by  drop,  until  a  delicate  scum  with  iridescent 
metallic  lustre  forms  on  the  surface.  The  amount  of  water 
required  will  vary  with  the  amount  of  staining  fluid  on  the 
preparation,  but,  in  a  general  way,  it  may  be  said  that  six  or 
eight  drops  will  be  required  if  a  seven-eighth-inch  square 
cover-glass  is  used.  The  amount  of  water  added  must  not  be 
sufficient  to  make  the  fluid  transparent. 

"The  staining  fluid,  thus  diluted,  is  allowed  to  remain  on  the 
preparation  for  two  or  three  minutes,  during  which  time  the 
real  staining  of  the  preparation  takes  place,  and  is  then  washed 
in  water. 

"The  blood  film  will  now  be  seen  to  have  a  blue  or  purple 
color,  and  if  examined  with  the  microscope  the  red  blood  cor- 
puscles will  be  seen  to  be  stained  blue. 

"The  next  step  is  to  develop  the  differential  staining  of  the 
various  elements  in  the  preparation.  This  is  done  by  washing 
the  preparation  in  water — preferably  distilled  water — until 
the  better  spread  portions  of  the  film  appear  yellowish  or  red- 
dish in  color.  Some  tap  waters  may  spoil  the  staining.  If 
desired,  the  process  of  differentiation  may  be  readily  observed 
by  placing  the  cover-glass  film  side  uppermost  on  a  slide,  cover- 
ing it  with  water,  and  examining  it  with  the  microscope  under 
a  low  magnifying  power.  The  red  blood  corpuscles,  which, 
as  before  stated,  at  first  have  a  blue  color,  will  become  greenish, 
then  yellowish,  and  finally  orange  or  pinkish  in  color,  depend- 
ing upon  the  depth  of  the  original  staining,  which  varies  with 
the  length  of  time  that  the  diluted  staining  fluid  has  been  al- 
lowed to  act  and  with  the  degree  of  its  dilution. 

"The  differentiation  by  washing  in  water  seems  to  be  essen- 
tially a  process  of  decolorization  by  which  some  of  the  blue 
constituent  of  the  dye  is  removed,  for  the  water  that  drains  off 
from  the  preparation  has  a  blue  color.    This  differentiation  or 


266  THE   STUDY  OF  MALARIA 

decolorization  proceeds  slowly,  and  may  require  one  or  more 
minutes,  depending  upon  the  intensity  of  the  staining  and 
upon  the  tint  sought  to  be  obtained  in  the  red  corpuscles. 

"It  is  apparent  from  the  above  that  with  a  little  experience 
with  the  method  the  color  of  the  red  corpuscles  may  be  made 
either  orange  or  pink,  as  the  operator  desires.  When  the  de- 
sired color  is  obtained  in  the  red  corpuscles  the  preparation  is 
then  quickly  dried  between  layers  of  filter  paper  and  mounted 
in  balsam.  It  is  important  to  stop  the  decolorization  by  drying 
the  preparation  as  soon  as  the  desired  tint  in  the  red  corpuscles 
is  obtained,  for  it  may  be  carried  too  far. 

"Dried  stains  on  the  upper  surface  of  the  cover-glass  may 
be  easily  removed  with  ordinary  alcohol. 

"In  the  light  of  the  foregoing  explanations  the  following 
summary  of  the  method  of  staining  blood  films  will  be  intelli- 
gible : 

"i.  Make  films  of  the  blood,  spread  thinly,  and  allow  them 
to  dry  in  the  air. 

"2.  Cover  the  preparation  with  the  staining  fluid  for  one 
minute. 

"3.  Add  to  the  staining  fluid  on  the  preparation  sufficient 
water,  drop  by  drop,  until  a  delicate  iridescent,  metallic  scum 
forms  on  the  surface.  Allow  this  mixture  to  remain  on  the 
preparation  for  two  or  three  minutes. 

"4.  Wash  in  water,  preferably  in  distilled  water,  until  the 
film  has  a  pinkish  tint  in  its  thinner  or  better-spread  portions 
and  the  red  corpuscles  acquire  a  yellow  or  pink  color. 

"5.  Dry  between  filter  paper  and  mount  in  balsam. 

"The  preparations  retain  their  colors  as  long  as  any  prepara- 
tion stained  with  aniline  dyes. 

"Unstained  blood  films  may  be  kept  for  some  weeks  without 
impairment  of  their  staining  properties.  Films  months  old 
will  probably  not  give  good  results. 

"The  red  cells  are  orange  or  pink  in  color.  Polychromato- 
philia  and  punctate  basophilia  or  granular  degeneration  are  well 
brought  out.  The  nucleated  red  cells  have  deep-blue  nuclei 
and  the  cytoplasm  is  usually  of  a  bluish  tint. 

"The  lymphocytes  have  dark  purplish-blue  nuclei  and  rob- 


DIAGNOSIS  267 

in's-egg-blue  cytoplasm,  in  which  a  few  dark  blue  or  purplish 
granules  are  sometimes  present. 

"The  polynuclear  neutrophilic  leukocytes  have  a  dark  blue 
or  dark  lilac-colored  nucleus,  and  the  granules  are  usually  of 
a  reddish-lilac  color. 

"The  eosinophilic  leukocytes  have  blue  or  dark  lilac-colored 
nuclei.  The  granules  have  the  color  of  eosin,  while  the  cyto- 
plasm in  which  they  are  imbedded  has  a  blue  color. 

"The  large  mononuclear  leukocytes  appear  in  at  least  two 
forms.  Each  form  has  a  blue  or  dark  lilac-colored  nucleus. 
The  cytoplasm  of  one  form  is  pale  blue,  and  of  the  other  form 
is  blue  with  dark  lilac  or  deep  purple-colored  granules,  which 
are  usually  not  so  numerous  as  are  the  granules  in  the  poly- 
nuclear neutrophilic  leukocytes. 

"The  mast-cells  appear  as  cells  of  about  the  size  of  poly- 
nuclear leukocytes,  with  purplish  or  dark  blue-stained,  irregu- 
lar-shaped nuclei,  and  with  cytoplasm,  sometimes  bluish,  in 
which  numerous  coarse  spheric  granules  of  variable  size  are 
imbedded.  These  granules  are  of  a  dark  purple  color  and  may 
appear  almost  black. 

"The  myelocytes  have  dark  blue  or  dark  lilac-colored  nuclei 
and  blue  cytoplasm,  in  which  numerous  dark  lilac  or  reddish 
lilac-colored  granules  are  imbedded.  In  leukemia  more  color 
differences  are  brought  out  among  the  leukocytes  than  by  the 
ordinary  methods  of  staining. 

"The  blood-plates  are  well  stained.  In  the  best  preparations 
they  appear  as  round  or  oval,  very  pale  blue  bodies  with  smooth 
contour,  containing  many  small  dark  lilac  or  blue-stained 
granules.  In  many  instances,  however,  only  the  deeply  stained 
granules  in  their  substances  are  visible.  They  are  usually  of 
a  diameter  of  one-third  to  one-half  of  that  of  a  red  blood 
corpuscle.  Frequently  they  occur  in  groups  or  masses,  and  at 
first  sight  may  be  regarded  as  precipitates." 

The  powdered  stain  keeps  well,  but  the  solution  after  a 
time  tends  to  lose  its  blue-staining  property,  hence  small  quan- 
tities only  of  the  solution  should  be  prepared.  If  too  intensely 
blue  at  first  some  old  stain  may  be  added  until  the  desired  tint 
is  obtained.    Films  prepared  upon  slides  are  more  easily  dealt 


268  THE   STUDY   OF   MALARIA 

with  than  those  upon  cover-glasses.  The  cedar  oil  is  dropped 
directly  upon  the  stained  film. 

The  examination  should  be  protracted  for  thirty  minutes 
before  being  pronounced  negative.  While  parasites,  if  present, 
are  usually  found  within  five  or  ten  minutes,  it  is  not  uncom- 
mon to  detect  the  first  organisms  after  a  search  of  twenty  to 
thirty  minutes. 

Cedar  oil  may  be  removed  from  the  film  by  wiping  gently 
with  a  soft  cloth  moistened  with  xylol. 

The  "thick  film  process"  is  occasionally  useful  where  the 
parasites  are  very  scanty.  The  blood  is  smeared  upon  the 
slide  in  a  much  thicker  layer  than  for  other  methods.  After 
drying,  a  little  distilled  water  is  added  and  allowed  to  remain 
fifteen  minutes,  which  causes  the  dissolution  of  the  hemoglobin. 
After  drying  again  the  film  is  stained  by  one  of  the  usual 
methods.  While  the  outlines  of  the  red  cells  are  still  visible, 
the  cells  are  transparent  and  parasites  may  be  detected,  though 
lying  under  several  cells.  The  advantage  of  this  method  is 
that  a  much  larger  volume  of  blood  may  be  examined  in  a 
shorter  space  of  time  than  is  the  case  with  the  thin  film. 

Flagella  are  much  more  easily  demonstrated  in  the  gametes 
of  the  estivo-autumnal  than  of  the  tertian  and  quartan  para- 
sites. The  crescent  becomes  oval  and  then  spheric  before 
exflagellation  is  observed.  To  encourage  this  process  the 
method  of  Stephens  and  Christophers118  is  most  practical.  A 
number  of  rather  thick  drops  of  blood  are  placed  upon  a  series 
of  slides.  The  slides  are  then  inverted,  with  the  hanging  drops 
over  holes  cut  in  blotting  paper,  moistened  with  water,  and 
spread  on  a  pane  of  glass.  A  series  of  moist  chambers  is  thus 
made.  A  slide  is  removed  at  intervals  of  five  minutes,  the 
blood  spread  in  the  usual  manner  and  stained.  Exflagellation 
is  also  observed  in  preparations  of  fresh  blood.  The  warm 
stage,  breathing  upon  the  specimen,  and  the  addition  of  a  little 
water  are  recommended  to  hasten  the  process. 

Sources  of  Error. — In  the  examination  of  blood  for  mala- 
rial parasites  there  are  several  objects  which  may  mislead.  Pit- 
falls are  probably  more  common  in  fresh  blood  than  in  stained 
films. 


DIAGNOSIS  269 

Vacuoles  and  retractions  of  hemoglobin  in  red  cells  of  fresh 
preparations  are  delusive  and  not  infrequently  mistaken  for 
the  young  hyaline  forms  of  the  parasite.  They  are  most  com- 
mon in  the  center  of  the  cell,  while  parasites  are  found  in  any 
portion.  Vacuoles  are  highly  refractive,  having  well-defined, 
clear-cut  edges ;  the  margins  of  the  parasites  are  dim  and  fade 
gradually  into  the  substance  of  the  red  cells.  The  vacuoles 
may  show  slight  changes  of  form,  but  do  not  possess  true 
ameboid  motion  nor  pigment.  While  the  vacuoles  are  per- 
fectly clear,  the  parasites  show  a  slight  opalescence.  In  stained 
specimens  areas  which  do  not  take  the  stain  may  deceive. 
These  areas  may  be  of  circular  form  in  the  center  of  the  cell, 
or  of  ring  form  surrounding  the  center,  or  may  be  oval,  horse- 
shoe shaped,  crucial  or  irregular.  When  present  they  are  apt 
to  be  abundant  in  some  portions  of  the  film  and  entirely  absent 
elsewhere. 

Crenations  of  red  cells  may  present  a  hyaline  appearance 
somewhat  resembling  an  ameboid  parasite.  Their  nature  may 
be  determined  by  changing  the  focus. 

Bent  or  buckled  corpuscles  occasionally  resemble  crescents. 
The  absence  of  pigment  and  the  size  of  corpuscle  should,  how- 
ever, enable  a  distinction.  Overlapping  of  the  corpuscles  may 
produce  a  ring  or  crescent  appearance  which  deceives  the  be- 
ginner. 

The  object  in  stained  spreads  which  proves  most  deceiving 
to  the  inexperienced  is  probably  the  blood  platelet.  These  cor- 
puscles may  lie  upon  or  within  the  red  cells,  in  the  center, 
near  the  periphery,  or  only  partially  enclosed  by  them.  They 
are  from  one-seventh  to  one-half  the  size  of  a  red  blood-cell, 
and  are  round,  oval,  or  elongated  in  shape.  They  are  often 
of  mulberrry  shape  and  reticular  structure,  and,  with  the 
Romanowsky  class  of  stains,  approach  more  nearly  purple  or 
lilac  than  the  characteristic  blue  of  the  parasites.  The  margin 
is  surrounded  by  a  pale  or  unstained  area  resembling  a  halo. 
There  is,  of  course,  an  absence  of  pigment  and  chromatin. 
Occurring  in  groups,  as  it  frequently  does,  it  has  not  rarely 
been  mistaken  for  a  sporulating  body,  and  isolated  for  a  free 


270  THE   STUDY   OF  MALARIA 

spore.  Bodies  resembling  free  spores  should,  however,  be 
disregarded  for  diagnostic  purposes. 

The  nuclei  of  nucleated  red  corpuscles  may  be  mistaken  for 
parasites,  but  this  should  rarely  occur  if  the  morphology  and 
staining  reactions  of  both  bodies  is  borne  in  mind. 

Cabot342  and  others  have  found  in  the  blood  of  patients 
afflicted  with  pernicious  anemia,  leukemia,  and  lead  poisoning 
ring-shaped  bodies  occurring  within  the  red  cells  and  not  unlike 
malarial  parasites.  Their  origin  or  significance  is  not  known, 
but  they  are  thought  to  represent  nuclear  remains. 

Pigmented  leukocytes  have  been  mistaken  for  parasites,  but 
the  ameboid  motion  of  the  former  in  fresh  specimens  and  the 
staining  reactions  in  dried  films  should  prevent  confusion. 

Hemokonia,  or  blood-dust,  may  be  confused  with  free  spores. 
They  are  small,  highly  refractive,  micrococcus-like  bodies  aver- 
aging one-half  micron  in  diameter  and  possessed  of  very  ani- 
mated motion.  .  As  stated,  free  spores  should  not  be  sought  for 
diagnosis,  and  bodies  resembling  them  should  be  ignored. 

Extraneous  dirt,  leukocyte  granulations,  and  stain  precipi- 
tates must  be  carefully  distinguished  from  pigment. 

The  amateur  in  examinations  of  malarial  blood  is  apt  to  be- 
come decidedly  discouraged,  even  when  he  has  satisfactorily 
mastered  the  technic  in  the  laboratory.  Most  students  gain  the 
impression  that  all  that  is  necessary  to  find  the  parasites  is  to 
locate  a  malarial  subject  with  any  form  of  the  disease  and 
obtain  the  necessary  blood  at  any  stage  of  parasitic  develop- 
ment, to  stain  it  properly,  and  to  inspect  it  under  a  high-power 
lens.  Usually  this  is  what  he  has  been  taught  by  text-books 
and  by  teachers,  and  when  he  fails  to  detect  the  characteristic 
organisms  in  undoubted  cases  of  malaria  he  is  disgusted.  The 
results  of  such  teaching  throw  discredit  upon  a  discovery  whose 
practical  importance  is  unsurpassed  in  modern  medicine. 

To  estimate  the  value  of  a  report  on  the  result  of  micro- 
scopic examination  of  the  blood  for  malarial  parasites  it  is 
always  desirable  to  know  something  of  the  experience  of  the 
examiner.  In  addition  to  competence  and  proper  technic  there 
are  several  factors  which  influence  the  result  of  the  examina- 
tion for  parasites.    The  most  important  of  these  are:  (a)  the 


DIAGNOSIS  271 

previous  administration  of  quinine;  (b)  the  stage  of  develop- 
ment of  the  organisms;  (c)  the  stage  of  the  disease;  (d)  the 
type  of  infection;  (<?)  race;  (/)  locality,  and  (g)  individual 
circumstances. 

(a)  The  previous  administration  of  quinine,  even  in  small 
quantities,  renders  it  almost  useless  to  examine  the  blood  with 
the  expectation  of  finding  parasites.  Even  where  the  quantity 
of  the  drug-  is  insufficient  to  have  any  effect  on  the  symptoms, 
it  will  ordinarily  cause  a  disappearance  of  the  parasites  from 
the  peripheral  circulation.  The  half-poisoned  parasites  which 
persist  in  some  instances  are  frequently  unrecognizable  with 
reference  to  type. 

(b)  The  quartan  parasite  is  nearly  evenly  distributed  in  all 
its  phases,  from  the  youngest  form  to  the  sporulating  body, 
throughout  the  superficial  and  deep  circulation.  Hence,  when 
dealing  with  this  type  it  makes  little  difference  at  what  period 
the  blood  is  examined.  But  with  the  estivo-autumnal  organism 
it  is  only  the  early  stages,  the  small  rings,  that  are  observed 
with  any  degree  of  frequency  in  the  peripheral  blood,  and  if 
the  examination  is  made  when  the  parasite  has  reached  a  later 
stage  of  development  it  will  probably  be  missed.  Instead  of 
resembling  the  quartan  parasite  in  habit  of  distribution  it  seems 
to  imitate  its  more  distant  relative,  the  Leishman-Donovan 
parasite.  Later  phases  of  the  simple  tertian  hematozoon  are 
less  commonly  found  in  examinations  of  the  peripheral  blood 
than  are  those  of  the  quartan,  but  are  much  more  frequently 
observed  than  those  of  the  estivo-autumnal.  Sporulating 
bodies  of  the  quartan  type  are  not  uncommon  in  the  cutaneous 
blood,  while  those  of  the  tertian  are  much  less  common  and 
those  of  the  estivo-autumnal  extremely  uncommon. 

The  frequency  with  which  crescents  are  detected  varies  with- 
in the  broadest  confines.  In  the  experience  of  some  they  are 
rare,  while  other  observers  note  them  frequently  in  estivo- 
autumnal  infections.  Tertian  gametes  are  not  rarely  observed 
in  the  blood  of  the  superficial  circulation,  while  quartan  gametes 
are  scarcely  found. 

(c)  In  acute  untreated  malaria  the  parasite  can  be  detected 
at  some  stage  of  its  growth  in  almost  100  per  cent,  of  cases. 


272  THE   STUDY  OF   MALARIA 

If  not  found  at  the  first  examination,  as  frequently  occurs, 
subsequent  searches  are  usually  successful.  On  the  contrary, 
in  chronic  malaria  the  parasites  are  far  from  constant  during 
the  stage  of  latency,  and  prolonged  search  may  fail  to  reveal 
them  during  the  relapse.  Parasites  are  often  absent  from  the 
peripheral  blood  of  malarial  cachectics.  In  the  paramalarial 
syndrome,  hemoglobinuric  fever,  the  parasites,  if  present  before 
onset,  afterward  disappear  in  the  majority  of  cases. 

(d)  The  behavior  of  the  different  kinds  of  parasite  in  their 
various  stages  has  been  referred  to.  As  a  rule,  the  quartan 
parasite  is  most  certainly  found  on  first  examination,  the  estivo- 
autumnal  least  so,  on  account  of  its  habit  of  resorting  to  the 
deep  circulation  when  approaching  maturity.  It  is  very  unfor- 
tunate for  rapid  diagnosis  that  the  estivo-autumnal  parasites 
are  less  readily  detected  than  those  of  the  benign  infections, 
but,  fortunately,  are  usually  easily  found  in  pernicious  cases  of 
estivo-autumnal  infection. 

(e)  That  malarial  parasites  are  found  less  frequently  and 
in  smaller  numbers  in  the  superficial  circulation  of  negroes  with 
malaria  the  writer  is  convinced,  though  the  difference  is  slight. 
This  opinion  is  confirmed  in  part  by  the  observations  of  Kulz,247 
who  found  malarial  parasites  much  less  frequently  in  his  negro 
malarial  patients  than  in  white. 

(/)  Along  the  Northern  borders  of  malarial  distribution  the 
parasites  are  probably  more  readily  detected.  This  may  be 
accounted  for  partially  by  the  greater  relative  frequency  of 
simple  tertian  infections.  Whether  the  more  northern  negro 
shows  the  same  scanty  distribution  of  parasites  in  the  peripheral 
blood  as  manifested  by  his  southern  brother  the  writer  has  no 
means  of  determining.  It  is  surprising  with  what  frequency 
crescents  are  found  in  higher  latitudes  in  the  blood  of  patients 
moving  from  highly  malarial  localities  where  crescents  are  not 
so  frequently  observed.  Whether  this  is  a  conservative  measure 
related  to  the  relative  rarity  of  anopheline  mosquitoes  cannot 
be  stated  positively,  but  it  is  known  that  the  life  histories  of 
animals  are,  in  some  instances,  peculiarly  interdependent,  espe- 
cially in  the  case  of  parasite  and  host. 

(g)   Why  it  is  that  in  certain  unquestionable  cases  of  malaria 


DIAGNOSIS 


273 


which  have  received  no  quinine  and  in  which  every  condition 
seems  favorable  to  finding  the  parasites  prolonged  and  repeated 
examination  shows  none  is  not  known,  but  such  cases  are  some- 
times encountered. 

As  before  said,  where  the  specific  can  be  withheld  and  re- 
peated examinations  made  by  a  competent  microscopist  if  not 
found  at  the  first  examination,  the  parasite  may  be  found  in 
almost  ioo  per  cent,  of  cases  of  malaria.  The  question,  which 
is  of  the  utmost  practical  importance  to  the  physician,  arises : 
In  what  proportion  of  cases  is  the  parasite  to  be  found  at  a 
single  examination?  On  this  depends  in  great  measure  the 
practical  value  of  Laveran's  discovery,  for  in  not  a  few  cases 
in  general  practice  for  reasons  of  convenience  the  examination 
cannot  be  repeated,  in  others  in  which  the  diagnosis  seems 
more  or  less  clear  urgent  symptoms  are  demanding  the  specific. 
The  two  factors  which  more  than  the  others  influence  the  result 
are  whether  or  not  the  patient  has  received  quinine  and  the 
phase  of  parasitic  development  attained  when  the  blood  is  with- 
drawn for  the  examination.  Neither  of  these  factors  is  always 
within  the  control  of  the  physician  who  desires  to  make  a  diag- 
nosis upon  examination  of  the  blood  taken  when  the  patient 
first  comes  under  his  observation.  Since  a  very  large  proportion 
of  the  malaria  of  the  land  is  treated  by  country  doctors,  the 
practical  value  of  a  diagnostic  test  is  largely  in  proportion  as 
it  is  applicable  by  them. 

With  reference  to  the  number  of  cases  in  which  the  parasite 
can  be  found  at  the  first  examination  the  writer  will  state  his 
experience.  From  a  record  kept  of  the  number  of  malarial 
cases  which  had  taken  quinine  in  some  form  before  coming 
under  observation  it  was  learned  that  this  reached  something- 
over  50  per  cent,  of  the  total  number  of  cases  treated.  The 
diagnosis  in  these  cases  was  obviously  based  upon  the  clinical 
history  and  the  therapeutic  test,  since  the  search  for  parasites 
in  the  blood  of  persons  having  received  quinine  is  so  discourag- 
ing that  this  has  not  been  done  in  routine  work,  but  only  in 
special  cases.  Allowing  for  errors  in  diagnosis  might  reduce 
this  number  to  50  per  cent.  A  specimen  of  blood  was  always 
taken  from  malarial  patients  who  had  not  recently  received 

18 


274  THE   STUDY   OF   MALARIA 

quinine  when  they  came  under  observation  for  the  first  time, 
irrespective  of  the  stage  of  the  access.  The  blood  from  frank 
cases  only  has  been  included,  no  cases  of  atypic  or  latent  mala- 
ria or  of  cachexia  figuring  in  the  result.  Parasites  were  found 
in  approximately  two-thirds  of  the  cases  and  the  examination 
was  negative  in  about  one-third.  No  difference  as  to  clinic 
course,  severity,  or  the  efficacy  of  quinine  could  be  detected 
between  the  cases  in  which  parasites  were  found  and  those  in 
which  none  were  observed.  From  this  experience  may  be  in- 
ferred that  in  localities  in  which  half  of  the  malarial  subjects 
take  quinine  in  some  form  before  consulting  a  physician  the 
parasite  can  be  detected  at  a  single  examination  of  the  periphe- 
ral blood  taken  at  random  with  respect  to  the  stage  of  parasitic 
growth  in  approximately  one-third  of  the  cases  only.  The 
prevalence  of  self -medication  with  quinine  products  depends 
largely  upon  local  custom  and  upon  the  energy  of  the  patent 
medicine  industry. 

The  experience  of  the  writer  being  somewhat  at  variance 
with  the  conventional  text-book  teaching,  he  feels  it  incumbent 
upon  him  to  cite  the  experience  of  others  in  this  matter  of  the 
most  vital  interest. 

Craig70  says,  "Often  if  the  blood  be  examined  but  once  none 
at  all  will  be  found." 

Fornario343  observes  that  the  parasites  are  missed  with  ex- 
treme frequency,  and  Soliani,147  in  an  analysis  of  612  cases 
under  his  care,  says  that  in  many  cases  the  first  examination 
was  negative. 

McElroy344  says,  "I  have  been  struck  with  the  frequency  with 
which  I  have  been  unable  to  find  parasites  in  cases  where  I 
am  strongly  impressed  with  the  malarial  nature  from  the 
clinical  history." 

Plehn345  states  that  the  parasites  are  frequently  lacking  in 
the  malaria  of  natives,  or  at  least  they  are  not  found  in  the 
peripheral  blood,  where  the  temperature  curve  is  typic  and 
pigmented  leukocytes  indicate  malaria. 

The  experience  of  Ewing27  at  Camp  Wikoff  is  interesting. 
"In  the  605  cases  of  malaria  the  plasmodia  were  found  in  the 
blood  in  335  cases,  while  in  270  cases  the  diagnosis  was  based 


DIAGNOSIS  275 

upon  the  clinical  history  and  the  discovery  in  the  blood  of  evi- 
dences of  malarial  infection.  The  evidences  of  malarial  infec- 
tion in  the  blood  consisted  ( 1 )  usually  in  the  presence  of  intra- 
cellular bodies  so  much  affected  by  quinine  that  their  exact 
type  could  not  be  positively  determined;  or  (2)  in  the  presence 
of  typic  pigmented  leukocytes;  or  (3)  in  chronic  cases  of  dis- 
tinct clinical  character  in  the  presence  of  marked  anemia." 

Leonard  Rogers,86  than  whom  there  is  no  more  competent 
observer,  says:  "As  long  ago  as  1896  I  showed  from  an  ex- 
amination of  100  cases  of  consecutive  malarial  fever  before  the 
administration  of  quinine  that  in  only  one-third  of  them  could 
the  malarial  parasite  be  found  by  means  of  a  prolonged  search 
of  a  single  blood  film." 

Delaney's346  experience  is  even  more  disheartening.  He  con- 
cludes :  "I  think  that  I  shall  be  supported  by  most  competent 
observers  in  India  that  this  ( 1 7  per  cent. )  about  represents  the 
percentage  of  success  in  finding  malarial  parasites  in  the  mala- 
rial fevers  of  India  at  a  single  examination,  and  on  this  point 
both  text-books  and  writers  on  the  subject  are,  I  consider,  very 
misleading." 

Such  quotations  from  practical  workers  and  keen  observers 
could  be  multiplied,  but  could  add  no  further  weight  to  the 
authority  of  those  cited. 

The  above  statements  are  not  meant  to  cast  the  slightest 
doubt  upon  the  etiologic  role  of  the  parasite  of  malaria,  or  its 
presence  in  every  case  of  acute  untreated  malaria,  or  its  great 
diagnostic  value  under  certain  circumstances,  but  are  intended 
to  demonstrate  that  the  detection  of  the  parasite  is  subject  to 
several  conditions.  In  probably  no  other  disease,  associated 
with  a  pathognomonic  sign  which  can  be  elicited  in  almost  100 
per  cent,  of  cases,  is  its  detection  so  dependent  upon  conditions 
beyond  the  control  of  the  physician. 

What  is  the  value  of  a  positive  result  of  examination  of  the 
blood  for  malarial  organisms?  This  parasite  is  thoroughly 
established  as  the  sole  cause  of  malaria,  and  its  pathogenic 
reputation  has  never  been  marred  by  rumors  of  etiologic  asso- 
ciation with  other  diseases,  but  is  the  parasite,  when  present, 


276  THE   STUDY   OF  MALARIA 

responsible  for  the  symptoms  which  instigate  the  blood  ex- 
amination ? 

In  localities  where  a  considerable  per  cent,  of  the  inhabitants 
carry  malarial  germs  in  their  blood  without  showing  malarial 
symptoms  it  is  manifestly  possible  that  parasites  might  be 
found  in  the  blood  of  such  inhabitants  during  the  course  of 
other  ailments.  And  such  is  actually  the  case  in  certain  regions 
with  a  very  high  endemic  index,  to  such  an  extent,  indeed,  that 
the  widely  experienced  Albert  Plehn,"  in  Cameroon,  declared 
that  the  presence  or  absence  of  malarial  parasites  in  the  blood 
of  the  West  African  coast  negro  is  of  no  diganostic  value. 

In  cases  of  coma  in  which  malarial  parasites  are  detected 
and  which  give  a  history  of  exposure  to  violent  heat  or  of  the 
abuse  of  alcohol,  it  is  not  infrequently  difficult  to  determine  the 
part  played  by  the  parasite.  In  cases  of  coma  accompanied  by 
malarial  parasites  in  the  blood  and  albumin  and  casts  in  the 
urine  the  diagnosis  may  be  obscure.  Fever  occurring  during 
the  puerperium  in  subjects  of  former  malaria  will  make  the 
thoughtful  physician  uneasy  for  a  short  while  at  least,  even  if 
parasites  are  found  on  blood  examination. 

These  are  mainly  problems,  however,  which  are  involved  in 
other  fields  of  diagnosis  and  serve  to  impress  the  fact  that  com- 
plications must  be  excluded  or,  if  found,  weighed.  While 
these  contingencies  should  not  be  lost  sight  of,  in  the  immense 
majority  of  cases  in  this  country  active  forms  of  the  malarial 
parasite  detected  in  the  blood  are  responsible  for  the  symptoms 
which  bring  the  patient  under  the  care  of  the  physician  or 
which  prompt  the  physician  to  make  the  examination. 

It  will  be  noted  that  the  word  active  is  emphasized.  What, 
then,  is  the  value  to  be  attached  to  the  discovery  of  gametes 
alone  ? 

Formerly  it  was  believed  that  the  sole  function  of  these  pecu- 
liar bodies  was  the  perpetuation  of  the  species  through  the 
mosquito  cycle.  Under  this  limited  view  the  detection  of 
gametes  alone  was  on  a  diagnostic,  par  with  anemia  and  spleno- 
megaly, sequelae  of  malaria,  and  not  necessarily  proof  of  exist- 
ing malaria,  even  latent.  Since  it  has  become  known,  however, 
that  under  certain  not  well  understood  conditions  the  macro- 


DIAGNOSIS  277 

gametes  can  immediately,  by  the  process  of  parthenogenesis, 
give  rise  to  pyrogenic  parasites  without  undergoing  the  mos- 
quito cycle,  our  views  must  be  modified,  and  these  forms  must 
be  regarded  clinically  as  the  parasites  of  latent  malaria.  Rela- 
tive to  active  malaria,  they  may  be  looked  upon  as  evidences 
of  past  and  potential,  but  not  necessarily  of  present,  active 
malaria. 

In  regard  to  the  number  of  parasites  in  a  given  film  of  blood 
the  following  classification  applies  to  estivo-autumnal  infec- 
tions : 

Abundant  when  there  is  an  average  of  two  or  more  parasites 
to  each  field  of  the  microscope ;  they  are  detected  immediately. 

Moderately  numerous  when  present  in  only  one  of  several 
fields ;  found  after  a  few  minutes'  search. 

Scanty  when  only  a  few  parasites  are  detected  in  the  entire 
film,  as  commonly  prepared,  aften  ten  to  thirty  minutes'  search. 

While  there  are  many  cases  of  estivo-autumnal  infection  in 
which  the  parasites  are  scanty,  large  numbers  of  estivo- 
autumnal  parasites  are  occasionally  observed  in  the  peripheral 
blood,  especially  of  pernicious  cases.  As  many  as  75  per  cent, 
of  the  red  cells  have  been  found  infested  in  several  cases  re- 
ported, and  Rogers44  mentions  a  rapidly  fatal  case  in  which 
the  blood  showed  more  parasites  than  erythrocytes. 

What  is  the  diagnostic  value  of  a  negative  result? 

The  writer  can  by  no  means  agree  with  those  who  maintain 
that  such  a  result  positively  excludes  a  diagnosis  of  malaria. 
The  failure  to  find  parasites  in  the  blood  of  a  single  film  taken 
without  reference  to  the  period  of  the  paroxysm,  while  of  some 
value,  is  not  conclusive,  and  if  the  patient  has  recently  received 
quinine  is  absolutely  worthless.  On  the  other  hand,  if  the  blood 
of  a  patient  who  has  not  recently  taken  quinine  be  examined 
repeatedly  by  a  competent  person  with  the  result  that  no  para- 
sites are  found,  it  is  very  strong  evidence  against  malaria. 
The  diagnostic  value,  then,  of  a  negative  finding  depends  upon 
the  presence  or  absence  of  the  conditions  which  have  been 
enumerated,  the  chief  of  which  is  the  administration  of  quinine. 

When  the  examination  of  the  peripheral  blood  is  negative 
puncture  of  the  spleen  has  been  advised,  as  the  parasites  in  all 


278  THE   STUDY  OF  MALARIA 

stages  are  easily  detected  in  the  blood  of  this  organ.  This  pro- 
cedure, however,  is  attended  with  some  degree  of  danger,  espe- 
cially of  hemorrhage,  and  should  be  resorted  to  only  in  cases 
where  an  immediate  diagnosis  is  imperative.  It  has  been  esti- 
mated that  the  mortality  of  aspiration  of  the  spleen  is  1^2  per 
cent.158  Many  fatalities  have  resulted  in  India  recently  from 
this  method  of  obtaining  blood  for  the  study  of  the  Leishmann- 
Donovan  parasites.44  When  decided  upon  the  following  pre- 
cautions should  be  observed :  An  aspirating  syringe  or  even 
an  ordinary  hypodermic  syringe  may  be  employed.  A  flexible 
connection  between  needle  and  nipple,  such  as  comes  with  the 
regular  antitoxin  syringe,  is  valuable  to  prevent  laceration  of 
the  capsule  of  the  spleen  in  the  event  of  sudden  respiratory 
movements.  Both  the  syringe  and  the  site  of  injection  should 
be  rendered  sterile.  Cutaneous  sensation  may  be  deadened  with 
cocaine  or  with  ethyl  chloride.  The  patient  should  be  in- 
structed to  hold  the  breath  on  deep  inspiration,  and  the  spleen 
should  be  steadied  against  the  ribs  and  diaphragm.  The  needle 
should  be  inserted  deeply  and  when  the  syringe  is  half  filled 
should  be  partially  withdrawn,  then  filled,  to  obtain  the  blood 
from  two  points.  The  operation  should  be  performed  quickly, 
that  the  patient  may  not  have  to  breathe  during  the  process, 
as  the  danger  of  laceration  is  thereby  increased.  Afterward 
the  cutaneous  puncture  should  be  sealed  with  collodion,  the 
patient  kept  at  rest  in  the  recumbent  position  for  twenty-four 
hours,  and  cold  applications  placed  over  the  region  of  the 
spleen.  A  dose  of  calcium  chloride  administered  half  an  hour 
before  the  procedure  might  lessen  the  tendency  to  hemorrhage. 

Upon  failure  to  discover  parasites  in  the  blood  there  are  two 
other  blood  signs  which  must  be  considered.  These  are  the 
presence  of  pigment  and  a  relative  increase  in  the  large  mono- 
nuclear leukocytes.  These  signs  are  termed  subsidiary  evi- 
dences of  malaria,  because,  being  secondary  in  diagnostic  im- 
portance to  the  parasites,  they  are  generally  called  upon  only 
in  the  absence  of  the  latter. 

Melanin  is  pathognomonic  of  malaria,  and  its  presence  is 
not  contingent  upon  the  stage  of  development  of  the  parasites 
■or  upon  the  previous  administration  of  quinine.    Theoretically, 


DIAGNOSIS  279 

therefore,  it  should  be  of  the  greatest  significance  in  the  diag- 
nosis of  malaria.  There  are,  however,  certain  circumstances 
which  detract  from  its  practical  value.  Free  pigment,  or  that 
lying  upon  the  red  blood-cells,  should  be  ignored  in  the  diag- 
nosis, as  it  cannot  be  distinguished  from  adventitious  detritus. 
Within  the  large  mononuclear  leukocytes,  the  leukocytes  in 
which  it  is  most  frequently  found,  it  must  be  carefully  distin- 
guished from  the  minute  pigment-like  granulations  which  may 
occur  normally  in  these  cells  to  the  number  of  one,  two,  or 
three  to  each  cell.  This  requires  a  considerable  degree  of 
experience  and  deceived  a  no  less  accurate  observer  than  Vin- 
cent.347 Coarse  granules  of  pigment  are  much  more  readily 
recognized,  especially  in  fresh  blood.  In  stained  films  precipi- 
tates may  prove  very  confusing.  Pigment  may  persist  for  two 
or  three  days  after  the  last  paroxysm  in  tertian  and  quartan 
infections,  and  for  a  much  longer  period  in  estivo-autumnal. 
It  is  more  valuable  as  a  diagnostic  sign  of  chronic  malaria  than 
of  acute. 

The  second  subsidiary  sign  of  malaria,  a  relative  increase 
of  the  large  mononuclear  leukocytes,  is  under  some  conditions 
a  valuable  aid  to  a  diagnosis.  The  proportion  of  large  mono- 
nuclear elements  in  the  differential  count  is  modified  by  certain 
factors  which  detract  somewhat  from  its  value. 

In  early  childhood  there  is  normally  an  increase  of  mono- 
nuclear leukocytes,  hence  this  sign  need  not  be  sought  for  in 
the  malaria  of  young  children. 

As  with  other  diagnostic  evidences  of  malaria,  this  sign  is 
unfortunately  more  constant  and  more  marked  in  tertian  and 
quartan  infections  than  in  estivo-autumnal. 

The  increase  of  the  large  mononuclear  leukocytes  in  malaria 
is  generally  in  inverse  proportion  to  the  height  of  the  temper- 
ature, being  most  decided  in  the  interval  and  may  be  absent 
during  pyrexia.  An  increase  may  be  wanting  also  early  in  first 
attacks. 

In  making  the  differential  count  the  leukocytes  lying  in  the 
middle  third  of  the  film  should  be  counted  and  the  slide  moved 
from  side  to  side  and  not  from  end  to  end.  If  the  colorless 
cells  are  calculated  at  random  or  only  near  the  ends  of  the 


280  THE   STUDY  OF  MALARIA 

smear  it  will  make  quite  a  difference,  particularly  in  the  relation 
of  the  small  lymphocytes  to  the  large  mononuclears,  and 
this  relation  is  significant.  It  is  an  interesting  experiment 
to  make  and  compare  differential  leukocyte  counts  at  both  the 
beginning  and  the  end  of  the  spread.  For  accuracy  at  least 
500  cells  should  be  counted,  though  250  give  a  fairly  correct 
estimate. 

Perhaps  the  chief  difficulty  in  the  procedure  is  the  almost 
arbitrary  distinction  between  the  small  mononuclear  and  the 
large  mononuclear  leukocytes.  An  investigation  of  the  litera- 
ture upon  the  subject  convinces  that  the  definitions  of  the  large 
mononuclear  leukocyte  are  essentially  different.  Furthermore, 
since  the  chief  difference,  size,  is  one  of  degree  only,  it  is 
obvious  that  there  is  much  room  for  error  in  the  application 
of  any  one  of  these  definitions  and  that  it  requires  a  good  deal 
of  experience  to  become  skilful  in  the  employment  of  this 
diagnostic  measure. 

When  there  is  evidence  of  leukocytosis  the  differential  count 
alone  must  not  be  relied  upon,  since  an  absolute  increase  may 
exist  under  these  circumstances  when  the  differential  count 
will  show  only  a  small  per  cent.  Here  the  absolute  count  must 
be  made  also. 

In  differentiating  malaria  from  typhoid  fever  the  differential 
count  is  of  value  only  in  the  first  two  weeks  of  a  fever,  since 
after  that  time  the  relative  proportions  of  the  leukocytes  are 
similar  in  the  two  diseases. 

Notwithstanding  its  difficulties,  the  differential  leukocyte 
count  made  by  an  experienced  examiner  may  render  important 
aid  in  the  diagnosis  of  malaria  where  the  parasite  cannot  be 
detected,  and  a  mononuclear  leukocytosis  reaching  1 5  per  cent, 
must  be  regarded  as  strong  evidence  of  malaria. 

Besides  the  presence  of  pigment  and  a  large  mononuclear 
increase  there  is  another  point  ascertained  by  microscopic  ex- 
amination of  the  blood,  this  is  the  presence  or  absence  of 
leukocytosis.  Between  malaria  and  typhoid  fever  this  point 
has  no  differential  value,  and  it  will  be  remembered  that  a 
leukocytosis  is  frequent  in  pernicious  malaria.  It  is,  however, 
in  septic  conditions  which  sometimes  so  closely  resemble  mala- 


DIAGNOSIS  28l 

ria  in  which  a  marked  leukocytosis  may  serve  to  exclude 
malaria. 

3.  The  Therapeutic  Test. — The  diagnostic  value  of  the 
therapeutic  test  has  been  known  since  the  days  of  Torti, 
though  neither  its  value  nor  its  limitations  are  yet  widely  real- 
ized. On  the  one  hand,  there  are  theoretic  and  ultrascientific 
writers,  apparently  valuing  a  microscopic  diagnosis  more  highly 
than  human  life,  who  advocate  withholding  the  specific  indefi- 
nitely until  the  parasite  may  be  found.  On  the  other  hand, 
there  are  physicians  who  continue  the  administration  of  quinine 
in  heroic  doses  for  days,  or  even  weeks,  in  fevers  which  do 
not  show  the  slightest  susceptibility. 

Here  diagnosis  and  treatment  meet  very  closely,  the  former 
encroaching  somewhat  upon  the  field  of  the  latter,  the  diagnos- 
tic test  often  becoming  a  therapeutic  and  life-saving  measure. 
The  therapeutic  test  is  of  especial  value  in  cases  which  have 
already  had  insufficient  quinine,  thereby  causing  only  the  dis- 
appearance of  the  parasites  from  the  superficial  circulation  and 
distortion  of  the  fever  curve.  In  these  cases  it  has  at  least  as 
much  standing  in  clinical  medicine  as  antisyphilitics  in  obscure 
cases  thought  to  be  syphilis  or  antitoxin  in  cases  of  suspicious 
angina  in  which  a  bacteriologic  examination  is  impossible. 
When  properly  applied  it  can  hardly  be  productive  of  harm. 

A  fever  which  resists  quinine  is  not  a  malarial  fever.  In 
order  to  test  the  resistance  of  a  fever  to  quinine  the  drug  must 
be  continued  for  a  sufficient  length  of  time  and  in  proper  doses 
at  suitable  intervals,  and,  what  is  most  important,  it  must  be 
absorbed. 

The  maximum  period  of  resistance  of  malaria  to  quinine  is 
ordinarily  stated  as  four  days.  As  far  as  the  writer's  observa- 
tions go,  they  tend  to  show  that  in  many  cases  the  fever  is 
broken  by  the  end  of  thirty-six  hours,  in  at  least  half  the  cases 
in  forty-eight  hours,  and  in  three-fourths  the  cases  in  sixty 
hours.  It  is  highly  probable  that  in  cases  of  malaria  persisting 
longer  than  four  days  the  specific  is  not  being  absorbed.  A 
case  is  recalled  in  which  the  fever  continued  notwithstanding 
the  administration  in  capsules  of  24  grains  of  a  soluble  salt  of 
quinine  during  the  twenty-four  hours   for  nearly   six   clays. 


282  THE   STUDY   OF   MALARIA 

Parasites  having  been  found  before  the  quinine  was  begun,  the 
drug  was  then  given  in  solution,  when  the  fever  responded  dur- 
ing the  seventh  day.  There  had  been  no  evidences  of  cin- 
chonism  until  the  solution  was  employed.  Cinchonism,  how- 
ever, is  not  a  guide  in  the  employment  of  the  therapeutic  test ; 
the  specific  is  directed  toward  the  parasites  and  not  toward 
the  patient,  and  patients  manifest  various  degrees  of  sensitive- 
ness toward  quinine. 

Owing  to  the  conditions  under  which  the  therapeutic  test  is 
usually  employed  it  is  better  to  use  moderate  doses  at  regular 
intervals  during  both  day  and  night.  Three  or  4  grains  every 
three  hours  are  sufficient.  Pills  and  tablets  of  quinine  should 
never  be  relied  upon ;  the  result  may  be  not  only  misleading  but 
dangerous.  Capsules,  if  fresh,  are  usually  satisfactory ;  a  few 
pin  punctures  in  each  end  aids  solution.  Where  the  fever  per- 
sists and  there  is  reason  to  believe  that  the  medicine  is  not  being 
absorbed  it  should  be  given  in  solution  or  even  intramuscularly. 

In  connection  with  the  therapeutic  test  the  law  of  Treille304 
is  interesting.     It  may  be  stated  as  follows : 

In  malarial  fever  quinine  given  in  a  single  proper  dose  at 
the  beginning  of  a  paroxysm  does  not  influence  that  paroxysm, 
but  always  suppresses  the  following  for  a  minimum  period  of 
five  days.  Designating  the  day  upon  which  quinine  is  admin- 
istered as  1,  the  minimum  duration  of  apyrexia  as  5,  and  the 
day  of  recurrence  as  1,  the  formula  may  be  graphically  repre- 
sented as  1-5-1.  In  the  case  of  quotidian  and  quartan  fevers 
the  duration  of  apyrexia  is  often  a  multiple  of  5.  The  formula 
is,  then,  1 -1115-1.  Treille  regards  as  a  proper  dose :  for  quartan 
fever,  25  centigrams;  for  quotidian,  2.5  grams,  and  for  tertian, 
2  grams. 

The  writer  cannot  vouch  for  the  details  of  these  propositions, 
but  the  general  principle  has  ample  support.  In  thorough  ac- 
cord are  the  recently  recorded  and  accurate  observations  of 
Cohen,305  who  ascertained  that  a  single  subcutaneous  injection 
of  15  grains  of  quinine  and  urea,  given  preferably  during  the 
paroxysm  or  shortly  after,  produced  an  apyretic  period  of 
approximately  six  and  a  half  days  or  approximately  thirteen 
days. 


DIAGNOSIS  283 

This  period  of  apyrexia  following  a  single  dose  of  quinine 
corresponds  closely  to  the  parthenogenetic  cycle.  The  con- 
quest of  the  schizonts  seems  to  be  a  signal  for  the  macro- 
gametes  to  lay  aside  the  conventionality  of  slow  sexual  repro- 
duction and  to  conscript  recruits  rapidly  by  parthenogenesis. 

Not  every  fever  which  discontinues  after  the  administration 
of  quinine  can  be  considered  malarial,  since  such  an  occurrence 
is  occasionally  coincidental.  Furthermore,  it  is  well  known  that 
quinine  has  no  little  antipyretic  influence  upon  certain  condi- 
tions, particularly  septic. 

It  is  probably  superfluous  to  say  that  the  diagnosis  of  malaria 
does  not  always  consist  alone  in  the  mere  mechanic  application 
of  a  single  test,  but  that  in  some  cases  the  keenest  clinic  judg- 
ment is  required.  Of  the  several  diagnostic  signs  which  we 
possess  each  is  valuable  and  each  has  its  limitations. 

It  should  be  a  routine  practice  to  take  a  specimen  of  blood 
from  each  fever  patient. 

In  dealing  with  a  disease  in  which  the  blood  examination 
affords  pathognomonic  evidence  and  for  which  we  possess  a 
specific  the  dilemma  is  often  faced,  where  the  examination  of 
the  first  specimen  of  blood  is  negative,  of  having  to  decide 
whether  it  is  best  to  wait  a  few  hours  for  an  absolutely  certain 
diagnosis  or  to  take  advantage  of  every  hour  and  begin  the 
treatment  immediately.  If  quinine  has  already  been  taken  the 
chances  are  that  further  examinations  would  also  be  negative, 
and  the  better  course  would  be  to  proceed  with  the  specific. 
If  quinine  has  not  already  been  taken  and  the  symptoms  are 
not  urgent  the  case  may  be  treated  symptomatically  for  a  little 
while,  during  which  time  the  blood  is  examined  at  appropriate 
intervals. 

In  hospital  practice  the  practical  value  of  the  blood  examina- 
tion for  malarial  parasites  is  inestimable;  in  general  practice, 
especially  in  the  rural  districts,  its  value  is  more  limited.  In 
general  practice,  especially  in  the  country,  the  therapeutic  test 
is  of  great  value ;  in  hospital  practice  it  is  less  often  justifiable. 


284  THE   STUDY   OF   MALARA 

DIFFERENTIAL  DIAGNOSIS 

The  differential  diagnosis  between  the  malarial  infections 
can  best  be  made  with  the  microscope.  In  only  one  type  of 
infection,  the  quartan,  either  single  or  double,  can  the  differ- 
ential diagnosis  be  made  clinically  with  certainty. 

The  differentiation  of  chronic  malaria  from  cachexia  is 
sometimes  very  difficult,  the  relation  being  one  of  disease  entity 
and  sequel,  and  the  difference  sometimes  one  of  degree  only. 

The  diagnosis  of  latent  malaria  must  be  based  solely  upon 
the  detection  of  parasites  in  the  blood.  Basophile  granulation 
of  the  red  cells  and  urobilinuria  cannot  be  relied  upon  as  evi- 
dences of  latent  malaria. 

Abscess  of  the  Liver. — Septic  conditions  are  very  often 
diagnosed  as  malaria ;  this  is  especially  true  of  hepatic  abscess. 
There  are  two  classes  of  cases  of  abscess  of  the  liver  that  may 
be  difficult  at  first  examination  to  distinguish  from  malaria; 
first,  where  the  local  symptoms  are  absent  or  not  well  defined ; 
second,  where  there  is  enlargement  of  both  liver  and  spleen  and 
a  history  of  both  dysentery  and  malaria.  The  fact  that  these 
patients  have  usually  been  drenched  unsystematically  with 
quinine  may  complicate  the  diagnosis.  In  typic  cases  of  hepatic 
abscess  there  is  usually  a  history  of  dysentery,  and  amebse  may 
be  present  in  the  feces.  There  is  usually  a  dragging  pain  in 
the  liver,  sometimes  referred  to  the  right  shoulder,  increase  of 
liver  dulness,  and  tenderness  on  pressure.  The  spleen  is  not 
necessarily  enlarged.  The  temperature  does  not  often  rise 
high,  and  there  is  apt  to  be  profuse  perspiration,  especially 
during  sleep.  On  microscopic  examination  of  the  blood  there 
is  usually  a  leukocytosis  to  be  found,  though  this  is  wanting 
in  a  few  cases,  and  its  absence  should  not  be  taken  to  exclude 
abscess.  There  are  neither  parasites,  pigment,  nor  a  relative 
increase  of  the  large  mononuclear  leukocytes.  Exploratory 
aspiration  is  valuable  in  some  cases.  Jaundice  is  a  very  variable 
symptom  and  may  be  misleading. 

Infective  endocarditis  may  present  periodic  paroxysms  of 
chill,  fever,  and  sweat.  The  physical  examination  of  the  heart 
and  the  microscopic  examination  of  the  blood  should  establish 
the  diagnosis. 


DIAGNOSIS  285 

Puerperal  Septicemia. — Women  who  have  had  malaria 
during  pregnancy  are  prone  to  suffer  relapses  during  the  puer- 
perium.  In  this  condition  malaria  is  not  infrequently  atypic : 
the  first  or  third  stages  of  the  paroxysm  are  sometimes  lacking 
and  complete  intermission  of  temperature  is  often  wanting. 
The  following  may  serve  to  differentiate  typic  cases  of  malaria 
and  puerperal  sepsis : 

Malaria.  Puerperal  Septicemia. 

Onset  from  a  few  hours  to  twenty-  Rare  after  the  fifth  day. 

one  days  after  labor. 

Often  a  history  of  malaria.  Malarial  history  usually  absent. 

Temperature    curve    more    or    less  Irregular. 

typic. 

Symptoms  decline  with  temperature.  No  relation  between  symptoms  and 

temperature. 

No  local  symptoms.  Local  symptoms  present. 

Blood  examination  positive.  Negative. 

Therapeutic  test  positive.  Negative. 

The  so-called  urethral  fever  may  be  accompanied  by  parox- 
ysms somewhat  resembling  those  of  malaria.  The  writer  has 
recently  seen  a  case  in  which  the  introduction  of  a  steel  sound 
every  other  day  was  accompanied  for  a  short  time  by  corre- 
sponding paroxysms  not  due  to  malaria.  The  differentiation 
from  malaria  should  present  no  difficulties. 

Perinephritic  abscess,  pyelitis,  cholecystitis,  and  other  septic 
processes  may  be  associated  with  fever  which  bears  a  more  or 
less  close  resemblance  to  that  of  malaria.  Local  symptoms,  the 
blood  examination,  and  the  therapeutic  test  rarely  leave  the 
diagnosis  in  doubt  but  a  short  while. 

Typhoid  Fever. — Since  Laveran's  discovery  and  since  the 
knowledge  of  the  prompt  efficacy  of  quinine  in  malaria  and  the 
value  of  the  Widal  reaction  have  become  thoroughly  established 
mistakes  in  the  diagnosis  of  typhoid  fever  and  malaria  should 
be  relatively  infrequent.  This  is  unfortunately  not  the  case. 
Witness  the  lesson  of  the  Spanish-American  War:  Of  20,738 
cases  of  typhoid  fever  occurring  in  the  American  army,  10,428, 
or  50.27  per  cent.,  were  correctly  diagnosed  by  regimental  or 
hospital  surgeons.  Most  of  the  remainder  were  called  malaria ; 
ten  thousand  mistakes  in  one  season,  and  the  board  of  inves- 
tigation concludes  that  in  recognizing  about  half  the  cases  of 


286  THE   STUDY   OF   MALARIA 

typhoid  fever  the  army  surgeon  probably  did  better  than  the 
average  physician  throughout  the  country  does  in  his  private 
practice. 

In  proportion  to  the  reliance  placed  upon  symptomatology  in 
the  differentiation  of  typhoid  and  malarial  fevers  so  frequently 
will  mistakes  occur.  Chills,  continued  fever,  bronchitis,  en- 
larged spleen,  slight  tenderness  and  gurgling  in  the  right  iliac 
fossa,  tympanites,  diarrhea,  the  Diazo  reaction,  delirium,  and 
the  typhoid  state  may  occur  with  either  disease.  Herpes  is 
strongly  indicative  of  malaria  and  rose  spots  of  typhoid  fever, 
but  these  spots  are  more  frequently  absent  than  present  in  the 
typhoid  fever  of  warm  countries. 

A  correct  diagnosis  must  rest  upon  the  results  of  the  exami- 
nation of  the  blood  and  the  therapeutic  test. 

The  number,  either  absolute  or  relative,  of  the  leukocytes 
is  not  as  valuable  in  this  connection  as  elsewhere,  and  if  the 
case  is  seen  early  the  diagnosis  may  be  made  before  the  Widal 
reaction  is  applicable,  but  this  latter  test  is  eminently  useful  in 
many  cases. 

Proper  prophylactic  precautions  should  be  observed  from 
the  start  in  cases  of  doubtful  diagnosis. 

Tuberculosis  is  sometimes  similar  in  its  course  to  malaria. 
It  is  especially  so  in  the  early  stage  when  the  local  signs  and 
symptoms  are  ill-defined  or  absent  and  the  bacillus  cannot  be 
detected,  and  in  the  stage  of  secondary  infection  when  septic 
symptoms  supervene.  Miliary  tuberculosis  has  not  infrequently 
been  mistaken  for  malaria.  For  the  diagnosis  between  tuber- 
culosis and  malaria  the  microscopic  examination  of  the  blood 
and  sputum,  the  physical  examination,  and  therapeutic  test  are 
usually  ample. 

Influenza  has  sometimes  been  confused  with  malaria.  If 
the  epidemic  occurrence,  different  seasonal  prevalence,  catarrhal 
and  other  symptoms  are  insufficient  upon  which  to  make  a 
diagnosis,  the  absence  of  characteristic  blood  findings  are  gen- 
erally conclusive. 

Yellow  fever  in  some  cases  so  closely  resembles  the  so-called 
bilious  remittent  fever  that  in  regions  where  both  diseases  occur 
the  differential  diagnosis  by  clinical  history  alone  is  impossible. 


DIAGNOSIS  287 

In  such  instances  the  microscope  becomes  an  instrument  of  the 
greatest  good  not  only  to  the  individual,  but  to  the  community. 

The  frequency  with  which  dysentery  is  associated  with  mala- 
ria as  a  complication  and  as  a  sequel  renders  the  microscopic 
examination  of  the  blood  very  important  in  these  cases. 

Patients  with  syphilis  manifesting  quotidian  fever  not  in- 
frequently receive  quinine  instead  of  antisyphilitics.  The 
microscope,  the  therapeutic  test,  and  the  history  should  form 
the  basis  of  the  diagnosis. 

Before  the  geographic  distribution  of  the  hookworm  and  its 
importance  in  the  production  of  anemia  became  recognized 
uncinariasis  was  not  distinguished  from  chronic  malaria  and 
cachexia.  The  detection  of  the  ova  in  the  feces  and  the  pres- 
ence of  eosinophilia  and  the  absence  of  parasites  and  the  sub- 
sidiary evidences  of  malaria  in  the  blood  render  such  a  mistake 
at  the  present  time  inexcusable. 

Leukemia  must  occasionally  be  taken  into  consideration  in 
the  differential  diagnosis  of  malaria,  in  which  case  the  micro- 
scopic examination  of  the  blood  is  absolutely  essential. 

The  differentiation  of  Band's  disease  from  chronic  malaria 
and  cachexia  may  be  extremely  difficult.  We  will  not  solve  the 
mysteries  of  splenomegaly  until  we  learn  a  safe  method  of 
obtaining  blood  from  the  spleen. 

THE  DIAGNOSIS  OF  PERNICIOUS  MALARIA 

It  is  only  since  Laveran's  revolutionizing  discovery  that  the 
diagnosis  of  pernicious  malaria  has  been  reduced  almost  to 
exactitude.  Cases  have  already  been  recited  where  the  parasites 
were  scanty  or  even  missed  in  the  blood,  but  these  are  only 
fare  exceptions.  In  the  immense  majority  of  cases  examina- 
tion of  the  peripheral  blood  will  reveal  the  presence  of  the 
organisms.  The  value  of  this  is  inestimable  and  is  paralleled 
only  by  the  importance  of  making  blood  examinations  in  all 
cases.  It  may  be  safely  said  with  Craig70  that  hundreds  of 
lives  have  been  sacrificed  to  pernicious  malarial  fever  which 
could  have  been  saved  had  an  examination  of  the  blood  been 
made.    It  is  not  extremely  uncommon  in  our  cities  for  subjects 


288  THE   STUDY  OF  MALARIA 

of  pernicious  attacks  found  in  coma  to  be  taken  to  the  police 
station  instead  of  the  hospital  and  the  true  condition  not  sus- 
pected until  the  patients  fail  to  "sober  up"  in  due  time,  when 
it  is  usually  too  late  for  treatment  to  avail. 

Negative  examinations  of  the  peripheral  blood  in  desperate 
cases  justify  risking  the  dangers  of  splenic  puncture. 

In  cases  showing  the  presence  of  parasites  complications 
must  be  rigidly  excluded.  In  some  cases  this  is  attended  with 
difficulties. 

In  comatose  malaria,  besides  the  evidence  obtained  by  an 
examination  of  the  blood,  a  history  of  exposure  to  or  attacks 
of  malaria,  the  general  appearance  and  age  of  the  patient,  the 
absence  of  atheroma,  the  early  elevation  of  temperature,  and 
perhaps  the  enlargement  of  the  spleen  and  slight  jaundice 
should  exclude  cerebral  hemorrhage.  The  differentiation  of 
malarial  coma  from  sunstroke  is  often  hard;  in  fact,  the  two 
not  infrequently  co-exist,  in  which  case  it  may  be  impossible 
to  apportion  the  etiologic  share  of  each  in  the  clinic  picture. 
Cardamatis287  states  that  in  this  type  of  pernicious  malaria 
coma  is  the  dominating  symptom,  while  in  sunstroke  are  ob- 
served coma,  convulsions,  delirium,  and  hyperpyrexia.  Uremic 
coma  may  simulate  that  due  to  malaria.  Unfortunately,  the 
urinalysis  throws  no  light  on  the  diagnosis,  as  in  both  condi- 
tions we  may  find  albumin  and  casts.  The  blood  examination, 
the  temperature,  and  the  anamnesis  serve  to  make  the  diagnosis. 
For  the  differentiation  of  alcoholic  from  malarial  coma  the 
blood  examination  is  essential.  The  history  may  be  of  value, 
but  the  odor  of  the  breath  may  be  misleading.  To  discriminate 
between  malarial  coma  and  diabetic  coma  the  presence  of  the 
parasites,  on  one  hand,  and  of  glycosuria,  on  the  other,  are 
sufficient.  In  differentiating  between  the  various  comas  with 
reference  to  malaria  two  points  should  be  remembered :  First, 
that  comatose  malaria  may  occur  in  persons  with  the  odor  of 
alcohol  on  the  breath,  and,  secondly,  that  coma  from  causes 
other  than  malaria  may  attack  malarial  cachectics.  To  distin- 
guish epilepsy,  opium  poisoning,  tetanus,  and  meningitis  from 
pernicious  malaria  should  rarely  present  difficulties  if  the  blood 
is  examined.     The  following  table  of  different  features  of 


DIAGNOSIS  289 

amblyopia  due  to  quinine  and  to  malaria  is  borrowed  from 
Manson  :09 

Quinine  Amblyopia.  Malarial  Amblyopia. 

History.— Quinine     taken     in     large  History.— Quinine    may    have    been 

doses,  not  less  than  30  grains.  taken,  but  not  necessarily  in  large 

doses. 

Onset.— Sudden,      accompanied     by  Onset.— Not  usually  sudden,  but  it 

deafness ;  both  eyes  are  affected.  may  be  so  if  hemorrhage  has  oc- 
curred in  the  macular  region. 
There  is  no  deafness,  and  both 
eyes   are  not  necessarily  affected. 

Pupils.— Widely   dilated,   and   while  Pupils.— React  to  light, 
loss   of  vision  continues   they  do 
not  react  to  light. 

Vision.— Completely  lost  for  a  time.  Vision.— Never  completely  lost. 

Ophthalmoscopic      Appearances.— A  Ophthalmoscopic       Appearances    — 

white  haze  over  fundus ;  cherry-  There  is  optic  neuritis ;  optic  disk 

red    spot    at    macula;    optic    disk  is     of     characteristic     grayish-red 

pale;     retinal     vessels     markedly  color;    retinal    hemorrhages    and 

constricted.  sometimes  vitreous   opacities. 

Termination.— Usually     some     per-  Termination.— Some    cases    recover 
manent    defect    in    the    field    of  completely;    in   others   greater  _ or 
vision    or   in    color    vision.     Cen-  less    permanent    defect    of    vision 
tral    vision    recovers    first;    optic  remains, 
disk  is  unusually  white,  and  reti- 
nal vessels  small.  .   . 

Treatment.— Stop     quinine.    Amyl-  Treatment.— Give  quinine, 
nitrite  has  been  recommended  to 
induce  dilation  of  retinal  vessels. 

Algid  attacks  sometimes  resemble  perforation,  or  typhoid,  or 
gastric  ulcers,  or  rupture  of  the  spleen.  The  microscope  and 
the  local  symptoms  should  render  the  diagnosis  certain.  The 
cases  resembling  appendicitis  and  peritonitis  have  been  men- 
tioned ;  here,  again,  the  microscopic  examination  of  the  blood 
may  save  lives.  In  countries  in  which  cholera  is  endemic  the 
diagnosis  between  this  disease  and  the  choleraic  type  of  perni- 
cious malaria  was  formerly  difficult  or  impossible.  Laveran's 
discovery  has  removed  this  difficulty  and  rendered  possible  a 
diagnosis  of  the  utmost  importance.  The  finding  of  the  hema- 
tozoa  differentiates  the  hemorrhagic,  bilious,  and  typhoid  types 
from  typhoid  and  yellow  fevers. 

DIAGNOSIS  OF  HEMOGLOBINURIC  FEVER 

This  is  usually  made  and,  as  a  rule,  correctly  before  the 

physician  arrives.    The  history  of  malaria,  the  fever,  vomiting, 

jaundice,  and  black  water  are  pathognomonic.     Though  the 

parasites  are  so  frequently  missed,  on  examination  of  the  blood 


19 


29O  THE   STUDY   OF   MALARIA 

there  is  usually  a  mononuclear  leukocytosis,  and  pigmented 
leukocytes  may  be  found. 

The  diagnosis  from  paroxysmal  hemoglobinuria  might  pre- 
vent difficulties.  In  this  rare  condition  the  attacks  usually  fol- 
low chilling  of  some  portion  of  the  body,  and  the  attack  is 
usually  of  short  duration  and  seldom  fatal.  In  hemoglobinuric 
fever  there  is  given  a  history  of  several  years  of  residence  in  an 
endemic  region,  repeated  attacks  of  malaria,  with  often  the 
presence  of  parasites,  pigmented  leukocytes,  and  a  mononuclear 
leukocytosis  in  the  blood. 

The  conditions  which  have  been  most  frequently  confounded 
with  hemoglobinuric  fever  are  yellow  fever  and  bilious  remit- 
tent fever. 

In  localities  where  yellow  fever  and  blackwater  fever  prevail 
their  differentiation  is  not  easy.  The  following  are  the  chief 
points  of  difference : 

Hemoglobinuric  Fever.  Yellow  Fever. 

Endemic.  Epidemic. 

One  attack  predisposes.  One  attack  confers  immunity. 

Occurs   usually  after   several  years      Attacks  also  new  comers. 

of  residence. 
Malarial  history  always  given.  May  be  no  history  of  malaria. 

Prodromata  common.  Uncommon. 

Icterus  intense,  early,  always  pres-      Icterus    usually    slight,    begins    on 
ent.  third  or  fourth  day;  may  be  ab- 

sent. 
Conjunctiva   jaundiced.  Usually  congested  at  first. 

Hemoglobinuria.  Albuminuria  or  hematuria. 

Blood  may  show  malarial  parasites,      Absent, 
pigmented  leukocytes,  and  mono- 
nuclear leukocytosis. 
Bilious  vomiting.  Vomit  clear  or  black. 

Hemorrhages  uncommon.  Relatively  common. 

Spleen  usually  much  enlarged.  Enlargement  slight. 

Increasing   pulse.  Pulse  retards  with  stationary  or  in- 

creasing     temperature       (Faget's 
sign). 
Albuminuria   from  beginning.  ,  Usually    appears     from     second    to 

fourth    day. 

A  rather  striking  coincidence  is  the  relative  immunity  of  the 
negro  to  both  diseases. 

Certain  cases  of  bilious  remittent  fever  present  points  of 
striking  similarity.  This  is  well  illustrated  by  the  following 
case  which  was  represented  to  me  by  the  messenger  and  by 
the  family  on  my  arrival  as  one  of  "hematuria"  : 


DIAGNOSIS  291 

A.  H.,  white,  male,  aged  thirty-nine,  timberman,  lived  in  a 
malarial  country  eighteen  years.  Never  had  hemoglobinuric 
fever.  He  had  been  having  chills  at  intervals  all  summer  and 
fall,  slight  fever,  "dumb  chills,"  and  slight  jaundice  for  three 
weeks ;  no  quinine  for  two  months ;  badly  salivated  from  seven 
large  doses  of  calomel  taken  several  days  ago.  Examination 
November  29,  1906,  four  and  a  half  hours  after  first  passage 
of  "bloody  water."  Temperature,  994/5;  pulse,  92;  marked 
jaundice  of  skin  and  sclera;  has  been  vomiting;  liver  region 
tender ;  spleen  extends  to  anterior  superior  spinous  process  and 
to  within  \y2  inches  of  the  umbilicus.  Blood  examination 
showed  two  large  pigmented,  intracorpuscular  parasites,  hemo- 
globin 65  per  cent.  Urine  "port  wine"  color,  acid  1.014;  nitric 
acid  test  for  albumin  negative,  biliary  coloring  matter  abun- 
dant, no  hemoglobin.  Microscopic  examination  negative.  Un- 
der quinine  treatment  the  urine  cleared  in  thirty-six  hours  and 
the  fever  left  in  a  few  days,  going  no  higher  than  ioil/2.  The 
anemia  and  enlarged  spleen  were  yet  present  when  I  last 
saw'  the  patient,  two  weeks  after  the  attack. 

The  following  scheme  will  help  to  differentiate  hemoglobin- 
uric  fever  and  bilious  remittent  fever: 

Hemoglobinuric   Fever.  Bilious  Remittent  Fever. 

Onset    sudden.  Onset  slower. 

Jaundice    develops    rapidly   and  be-      Jaundice  develops  more  slowly  and 

comes  intense.  is  not  so  intense. 

Parasites  frequently  absent.  Parasites  usually  present. 

Albuminuria  constant.  Albuminuria  not  constant. 

Urine  colored  by  hemoglobin  or  its      Urine  colored  by  bile. 

derivatives. 

The  differential  diagnosis,  as  attempted  by  some  writers, 
from  "quinine  poisoning  in  malarial  subjects"  is  futile  and  im- 
possible, as  this  condition  is  a  mode  of  hemoglobinuric  fever. 


CHAPTER  VII 


PROGNOSIS 


Spontaneous  Recovery. — It  is  a  familiar  fact  that  malaria, 
after  the  manner  of  other  infectious  diseases,  not  infrequently 
undergoes  what  is  termed  spontaneous  cure.  Physicians  in 
malarial  regions  often  see  patients  whose  paroxysms,  typic  and 
with  characteristic  periodicity,  have  ceased  without  medication 
or  after  nothing  but  a  purgative  dose. 

It  is  doubtful,  however,  whether  this  cessation  may  with  pro- 
priety be  termed  a  cure.  In  the  majority  of  instances  relapses 
follow  at  shorter  or  longer  intervals.  It  is  better,  therefore, 
for  practical  purposes  to  consider  this  but  a  transition  from 
active  malaria  to  latency.  The  greater  frequency  with  which 
gametes  are  found  after  the  so-called  spontaneous  recovery 
justifies  this  assumption. 

Spontaneous  cure  occurs  more  frequently  in  tertian  and 
quartan  infections.  This  statement  applies  merely  to  the  tem- 
porary cessation  of  paroxysms  and  not  to  the  tendency  to  re- 
lapse. 

It  is  more  frequently  observed  in  the  negro  than  in  the  white 
race,  permanent  cures  occurring  not  rarely  in  the  former  race 
in  the  absence  of  all  medication. 

Sex  may  exert  a  slight  influence  upon  the  tendency  to  spon- 
taneous recovery,  the  female,  on  account  of  less  severe  exposure 
to  deleterious  influences,  probably  manifesting  a  greater  dis- 
position. 

The  discontinuance  of  paroxysms  may  be  sudden  or  more 
often  gradual,  the  accesses  becoming  less  severe  or  the  interval 
longer,  or  in  infections  with  more  than  one  generation  of  para- 
sites one  may  be  suddenly  destroyed,  the  others  later. 

Prognosis. — This  is  influenced  to  some  extent  by  locality. 
It  is  manifest  that  in  regions  where  only  the  tertian  and  quartan 

292 


PROGNOSIS  293 

infections  are  prevalent  the  mortality  is  less  than  where  severe 
estivo-autumnal  fevers  are  widespread.  There  is,  furthermore, 
quite  a  difference  in  the  mortality  rate  in  countries  where  the 
estivo-autumnal  infections  are  equally  distributed. 

Race  as  a  factor  in  the  mortality  of  malaria  has  already  been 
dealt  with. 

A  majority  of  deaths  from  malaria  occur  in  children.  There 
is  no  doubt  but  that  many  children  die  of  malaria  which  has 
not  been  diagnosed  in  time.  In  the  young  pernicious  symptoms, 
especially  cerebral,  are  prone  to  supervene,  or  the  attack  may 
be  followed  by  extreme  anemia  and  dropsies.  Malaria  is  like- 
wise much  more  serious  in  advanced  age  than  in  the  interme- 
diate ages. 

Occupation  and  social  conditions  play  a  part  in  prognosis. 
Excessive  toil  and  exposure  may  render  pernicious  attacks 
otherwise  benign,  and  timely  treatment,  usually  resorted  to  by 
the  better  classes,  enhances  the  chance  of  recovery. 

The  outlook  is  probably  more  favorable  in  attacks  occurring 
without  the  malarial  season  than  within. 

Manifestly  the  condition  of  the  patient  with  reference  to  the 
results  of  previous  disease  is  of  importance.  Anemia,  alcohol- 
ism, dysentery,  and  other  conditions  not  fully  recovered  from 
contribute  gravity  to  the  prospect. 

The  type  of  malarial  infection  is  of  the  greatest  importance. 
In  the  tertian  and  quartan  types  it  is  only  very  rarely  that 
serious  symptoms  result.  It  is  not  yet  certainly  known  in 
which  variety  of  estivo-autumnal  infection  the  prognosis  is 
most  grave.  While  Marchiafava  and  Bignami162  and  Manna- 
berg141  hold  that  the  tertian  estivo-autumnal  infections  are 
most  often  attended  with  danger,  Craig70  and  Wright38  main- 
tain the  opposite  view. 

Postponement  and  anticipation  of  the  paroxysms  were  for- 
merly regarded  as  favorable  and  unfavorable,  respectively. 
However,  owing  to  the  irregularity  of  the  estivo-autumnal 
fevers,  these  can  be  said  strictly  to  be  properties  of  tertian 
and  quartan  infections  only,  and  are  consequently  of  little  prog- 
nostic import.  Violent  headache,  somnolence,  sighing  respira- 
tion, slight  mental  aberration,  defective  articulation  and  vision, 


294  THE    STUDY   OF   MALARIA 

cold  surface,  and  rapid,  feeble  purse  are  some  of  the  symptoms 
which  forebode  evil. 

The  prognostic  value  of  the  microscopic  examination  of 
the  blood  is  limited.  While,  as  a  general  rule,  the  severity  of 
the  attack  is  in  proportion  to  the  number  of  parasites,  these 
are  sometimes  scanty  in  the  peripheral  circulation  even  in  grave 
cases.  Sporulating  and  advanced  stages  of  estivo-autumnal 
parasites  are  rarely  seen  in  the  superficial  blood  except  in 
extremely  severe  cases. 

Delaney346  regards  a  reduction  of  leukocytes  to  or  below 
1,500  as  of  grave  prognostic  value.  The  writer  is  unable  to 
verify  this  from  his  experience,  since  in  his  cases  of  pernicious 
malaria  there  has  existed  a  leukocytosis. 

While  in  tertian  and  quartan  infections  a  paroxysm  may  be 
predicted  approximately  from  the  results  of  blood  examination, 
such  an  attempt  with  estivo-autumnal  malaria  may  prove  mis- 
leading. An  impending  paroxysm  dependent  on  mature  para- 
sites in  the  visceral  circulation  cannot  be  foretold. 

Intercurrent  diseases  complicating  malaria  aggravate  the 
prognosis.  This  is  especially  the  case  in  chronic  malaria  and 
cachexia,  with  which  pneumonia,  dysentery,  and  other  diseases 
form  frequently  fatal  associations. 

The  gravity  of  pregnancy  as  a  complication  of  malaria  has 
been  considered. 

In  nephritis  of  malarial  origin  the  prospect  is,  as  a  rule, 
good.  If,  however,  the  patient  is  repeatedly  subjected  to 
malaria  or  other  harmful  influences  the  prognosis  is  not  propi- 
tious. 

The  prognosis  of  the  nervous  sequelae  is  ordinarily  favor- 
able. The  various  paralyses  and  mental  symptoms  are  gener- 
ally transitory,  but  may  occasionally  become  persistent.  Bulbar 
symptoms  are  usually  slow  to  disappear. 

The  course  of  chronic  cachexia  may  be  extended  for  years ; 
acute  cachexia  runs  a  more  rapid  course.  In  mild  cases  a 
change  of  climate  and  tonic  treatment  do  a  great  deal  for  the 
patient;  advanced  cases  rarely  recover.  Death  may  occur 
from  exhaustion,  but  is  more  commonly  due  to  pernicious 
malaria  and  to  complications,  of  which  the  most  frequent  are 


PROGNOSIS  295 

pneumonia  and  nephritis.  Hence  the  danger  to  the  cachectic  is 
not  confined  to  the  malarial  season,  but  he  is  in  danger  through- 
out the  entire  year. 

Mortality. — The  true  mortality  of  malaria  is  difficult  to 
estimate.  While  statistics  are  not  lacking,  the  different  condi- 
tions under  which  they  are  compiled  must  be  considered,  some 
being  from  charity  hospitals,  some  from  private  practice,  some 
from  military  practice,  from  various  localities,  etc.  It  is,  fur- 
thermore, undoubtedly  true  that  a  considerable  proportion  of 
malarial  cases  does  not  come  to  the  notice  of  physicians.  The 
variety  of  forms  which  malaria  assumes  is  another  obstacle. 
It  is  probable  that  many  cases  ascribed  to  complications,  fan- 
cied or  real,  are  due  to  malaria. 

Bearing  these  points  in  mind,  the  following  figures  are  pre- 
sented, showing  a  mortality  of  2.89  per  cent. : 

Author.  Locality.  Cases.  Deaths. 

Laveran1   Turko-Russian  War . .  140,000  1,092 

Laveran1   Constantine    1,310 

Laveran1   Italian  Army 4,856  13 

Schellong"2    New  Guinea 1,954  22 

Ross"8    Greece    960,048  5,916 

Ross349    Hong  Kong 7,352  984 

Ewing27  Camp  Wikoff 605  39 

Smart76    Civil  War 1,373,355  15,423 

Travers38  Malay  States 3,397  348 

Terburgh84   Dutch  Indies 2,308,128  114,490 

Cardamatis68    Athens   22,618  15 

Koch34  Grosseto    281 

Koch172    East   Africa 63  2 

Hagen350    Papua  301  23 

British  Colonial  Reports351. British   Colonies 12,617  618 

Wright38    British   Malaya 17,468  680 

Haw352  Baberton    449  l4 

Hope40  North    Bengal 1,784 

Laveran3"  Algiers   98,774  7,432 

Gorgas354   Panama   1,055  5 

Erni81 Dutch  Indies 116,879  73* 

United  States  Marine  Hospital35".  .General    6,618  20 

Various  Hospital  Reports Southern    States 1,294  30 

German  Protectorate  Reports356... German    Protectorates  5,003  32 

Malaria  Society37 Italy    22,792 


120 


5,109,001       148,055 

Prognosis  of  Pernicious  Malaria. — The  prognosis  of  per- 
nicious malaria  is  extremely  grave.  It  depends  upon  the  physic 
condition  and  age  of  the  patient,  the  type  and  severity  of  the 
attack,  and  the  promptness  and  efficiency  of  the  treatment. 


296  THE    STUDY    OF   MALARIA 

Anemia  from  previous  attacks  of  malaria  or  other  causes, 
alcoholism,  or  organic  disease  of  important  viscera  add  to  the 
gravity  of  the  case.  The  cerebral  types  are  less  serious  in  the 
young  and  vigorous,  very  fatal  in  the  aged.  As  a  rule,  patients 
seen  early  and  treated  skilfully  and  energetically  have  a  better 
chance  for  life,  but  many  cases  end  fatally  in  spite  of  the  best 
and  most  timely  treatment. 

The  number  of  parasites  in  the  peripheral  circulation  is  not 
always  a  reliable  guide  as  to  the  severity  or  progress  of  the 
attack.  With  apparent  amelioration  of  the  symptoms  the 
physician  should  be  circumspect  in  his  prognosis  and  bear  in 
mind  the  possibility  of  further  paroxysms. 

In  the  writer's  opinion,  the  algid  type  is  the  most  lethal, 
the  typhoid  and  the  dysenteric  least  so,  though  this  is  not 
exactly  in  accord  with  Colin,291  who  arranges  the  types  accord- 
ing to  the  following  descending  scale  of  gravity :  Syncopal, 
algid,  cardialgic,  delirious,  comatose,  icteric,  choleraic.  Schel- 
long92  regards  the  comatose  as  the  most  dangerous,  and  Le 
Dantec,26  the  delirious  and  algid. 

Parry357  states  that  average  mortality  of  pernicious  malaria 
is  1  out  of  every  8  cases;  Wharton358  estimates  it  as  1  of  every 
12  or  15;  Haspel86  and  Borius,149  one-third;  Pampoukis,86 
21.4-25.4  per  cent.;  Le  Dantec,226  20-50  per  cent,  and  Cres- 
pin,"4  20-70  per  cent.  The  algid  type  is  said  by  PampoukisS6  to 
be  fatal  in  55.5  per  cent,  of  cases.  Cardamatis287  states  that 
the  comatose  variety  is  fatal  in  20-40  per  cent. ;  Bergeand309 
believes  the  mortality  of  this  type  to  be  50  per  cent. 

The  following  list  of  27,039  cases  of  pernicious  malaria, 
compiled  from  the  literature,  shows  a  mortality  of  26.6  per 
cent.  The  first  column  of  figures  shows  the  number  of  cases, 
the  second  the  number  of  fatalities : 

Number  of       Number  of 
Cases.  Deaths. 

Laveran1    104  53 

Bailly360 886  341 

Nepple86    14  6 

Antonini  and  MonarcT -. 39  9 

Maillot80    186  38 

GralP6    117  75 

Burot  and  Legrand212 210  142 

Smart70   16,209  4.164 

Travers38 260  81 


PROGNOSIS  297 

Number  of       Number  of 
Cases.  Deaths. 

Martirano150    19  9 

Pezza84    2  1 

Tanzarella84  31  8 

Thayer  and  Hewetson29 3  2 

Plehn5   10  1 

Maillot362 7  6 

Theophanidis362 5  2 

Cardamatis363  3  2 

Pampoukis362   52  20 

Billet161    40  2 

Segard79    24  15 

MaureP   156  77 

Caccini147    135  56 

Martirano147 6  3 

Charity  Hospital,  New  Orleans361 8  6 

Neer166 3  3 

Celli83    8,032  1,879 

Cardamatis68    So  9 

Colonial  Reports351 252  133 

Kelsch  and  Kiener178 89  51 

Albini82 87 _ii 

27,039  7,205 

Six  hundred  and  eighty-nine  cases  of  specified  type  give 
the  following  respective  mortalities : 

Comatose.  Delirious.  Algid.  Typhoid.  Ataxic. 

Maillot86    77-14  61-12  48-12 

Schellong"    7-6 

Plehn5   10-1 

Maillot362    ....  7-6 

Theophanidis362    ....  5-2 

Cardamatis363 ....  3-2 

Pampoukis287    52-20 

Billet151    ....  ••••            40-2 

MaureP    279-103  ....  78-23            ....            22-17 

Neer156 3~3  

Total   428-147  61-12  141-45            40-2            22-17 

34%  20%  32%             5%             77% 

The  Prognosis  of  Hemoglobinuric  Fever. — The  prognosis 
of  hemoglobinuric  fever  is  grave,  and  should  be  "guarded  and 
Delphic."  Probably  the  most  valuable  prognostic  sign  is  the 
quantity  of  urine ;  the  chemic  analysis  and  microscopic  exami- 
nation are  not  of  great  value  in  prognosis.  Anuria,  the  most 
dreaded  symptom,  is  to  be  feared  if  the  daily  quantity  of  urine 
falls  below  200  cc.  If  suppression  supervenes  the  outlook  is 
extremely  serious  and  is  unfavorable  in  proportion  to  early 
onset.     When  a  patient  is  tided  over  a  period  of  suppression, 


298  THE    STUDY   OF   MALARIA 

as  occasionally  happens,  he  usually  dies  during  convalescence 
of  exhaustion,  subsequent  nephritis,  or  embolism. 

Excessive  and  uncontrollable  vomiting  is  a  bad  omen,  ex- 
hausting the  sufferer  and  interfering  with  nutrition  and  medi- 
cation. Diarrhea  is  probably  in  many  cases,  with  suppression 
or  a  tendency  thereto,  a  life-saving  measure,  and  may  be  par- 
tially responsible  for  the  relative  rarity  of  uremic  symptoms 
under  these  circumstances.  Singultus  is  present  in  a  majority 
of  fatal  cases,  and  when  obstinate  is  always  unfavorable.  Re- 
mittent or  intermittent  temperature  is  usually  favorable.  Som- 
nolence, with  diminishing  amount  of  urine ;  coma,  especially  of 
early  onset,  petechias,  epistaxis  or  other  hemorrhage,  and  algor 
forebode  evil. 

Thrombus  formation  in  the  heart  or  large  vessels  may  cause 
sudden  death  when  the  patient  is  thought  to  be  progressing 
favorably.  Plehn5  believes  that  loud  heart  murmurs  accom- 
panied with  weak,  irregular  pulse  denote  heart  thrombus.  This 
condition  is  almost  certainly  fatal,  usually  in  five  to  eight  days. 

The  larger  the  share  partaken  by  quinine  in  the  etiology  of 
the  individual  case  the  better  the  prognosis,  provided  the  case 
is  not  further  aggravated  by  quinine. 

Cases  occurring  in  victims  of  malarial  cachexia  or  of  com- 
plications are  usually  more  serious. 

The  mortality  varies  unaccountably  from  year  to  year,  some 
seasons  evincing  a  series  of  mild  cases,  others  an  appalling 
mortality.  In  a  certain  parish  of  Louisiana  in  1867  many 
cases  are  said  to  have  occurred,  of  which  not  less  than  95  per 
cent,  died.366  Fisch,191  who  placed  the  mortality  on  the  Gold 
Coast  at  20  per  cent.,  states  that  until  two  or  three  decades 
previously  nearly  all  who  were  attacked  died.  On  the  other 
hand,  Banks210  makes  the  well-nigh  incredible  statement  that 
he  treated  over  100  cases  in  the  Congo  State  without  a  death. 

Pampoukis96  gives  the  mortality  of  blackwater  fever  as 
6.6  per  cent. ;  Crosse,4  20  per  cent. ;  Kanellis,867  22.4  per  cent. ;. 
Berenger-Feraud,96  23.1  per  cent.;  Barthelemy-Benoit,96  25 
per  cent. ;  Bertrand,229  25  per  cent. ;  Carre,191  27  per  cent. ;  Cas- 
san,96  32.1  per  cent. ;  Michel,368  33  to  50  per  cent. ;  Schellong",191 
42  per  cent. ;  Reynolds,367  50  per  cent. ;  Scott,367  60  per  cent. 


PROGNOSIS  299 

The  following  list  of  6,037  cases,  with  1,268  deaths,  shows 
a  mortality  of  21  per  cent.  It  is  compiled  from  various  sources. 

The  first  column  of  figures  shows  the  number  of  cases,  the 
second  the  number  of  deaths: 

TREATED    WITH    QUININE,    1821    CASES,    472    DEATHS,    25.9% 

Number  of  Number  of 

Cases.  Deaths. 

Vieth8  14  3 

Dryepondt8   28  1 

Mense234 22 

Powell234    9  7 

Gelpe234 3  2 

Diesing234 2  2 

Hagge234 7  2 

Schellong234 7  3 

Reynolds234    1  1 

Doering187    6 

Hanley184   13  3 

Moffatt263 '..       9  2 

Gorgas354   20  3 

Steudel96    18  3 

Malone389  120  14 

Brem215 14  2 

Coste370 IS  7 

Steggall371    3 

Woldert240   5 

Otto63   1 

Schlayer222 1 

Austin372 1 

Herrick261    8 

Curry186 1  1 

Burot  and  Legrand225 3  1 

Cardamatis208    1,352  354 

Broden242  12  7 

Theophanidis373    23  14 

Oeconomou373 18  5 

McDaniel374  _8_5_  35 

TREATED  WITHOUT  QUININE,  1006  CASES,  112  DEATHS,  11.1% 

Number  of  Number  of 

Cases.  Deaths. 

Tomaselli232 30  6 

Navarre8    2 

Henric376    2 

Kohlstock376    48  8 

Koch172 16  3 

Hopkins260  6  1 

Bertrand229    21  2 

Ollwig49   15 

Wittrock49  4  1 

Ziemann49    12  4 

A.  Plehn1"   53  5 

Kleine223  15  1 

Krauss199    15 

McElroy214 25  4 

Goltman  and  Krauss1'" 12  9 


300  THE    STUDY    OF   MALARIA 

TREATED  WITHOUT  QUININE,  1006  CASES,  112  DEATHS,  11.1% 

Number  of  Number  of 

Cases.  Deaths. 

Malone369  35 

Coste370 10  4 

Hearsey266    15  4 

Seal258   6  1 

Ruge239 1 

Dryepondt  and  Vancampenhout228 1 

Howard218   1 

Ketchen238   1 

Masterman"  1  1 

Herrick251    1  1 

Curry186    1  1 

Cardamatis206    456  33 

Ensor377    «  I 

Broden242  25  2 

Pancot242    7  z 

Theophanidis373    9 

Oeconomou373  31  2 

McDaniel374  93  16 

F.  Plehn6 25  1 


TREATMENT    MIXED    OR    NOT    RECORDED,    3210    CASES,    684 

DEATHS,  21.3% 

Number  of     Number  of 

Cases.  Deaths. 

Kanellis232    ' 20  4 

Poole8  56  15 

Rothschuh8   20  18 

GuioF8  185  49 

Gouzien370    53 

Meixner49    40  6 

Hofft49    14  6 

Wendland49   10 

Daniels67    184  41 

Wellman56  34  5 

Ipscher90    20  1 

Krueger90    n  2 

Simon90    17  3 

Kerr  Cross380 27  9 

Osborn14    10  5 

Berenger-Feraud"    286  66 

O'Neill98 50  2 

Burns235   16  6 

Shropshire267  177  35 

Dempwolff381 17  2 

Lipari202   19  5 

Gouducheau245    IS  4 

Cochran382   642  158 

Kelsch  and  Kiener178 109  35 

Bolton383    175  38 

Grail256   113  13 

Forde384   2  1 

Grenet373  68  8 

Rousseau373   • 22  6 

Carmouze373    30  9 

Mericourt373    22  3 

Koryllos373  28  5 

Pampoukis373    156  35 


PROGNOSIS  301 

TREATMENT  MIXED  OR  NOT  RECORDED,  3210  CASES,  684 
DEATHS,  21.3% 

Number  of      Number  of 
Cases.  Deaths. 

Cardamatis385    30  6 

Parathyris373  23  3 

Prout38S 24  8 

Jacobs387 147  16 

DeCruz388  13  6 

DeBlasi389 3 

Orme390 2 

Thompstone391    27  5 

German  Protectorate  Reports356 293  45 

Total    6,037  1.268 

F.  Plehn5  asserts  that  mortality  is  highest  in  first  attacks, 
but  the  following  table  of  Daniels57  does  not  bear  him  out : 

Of  136  first   attacks 31  or  22.7  per  cent,  were  fatal 

Of    33  second  attacks 8  or  24.0  per  cent,  were  fatal 

Of     15  third  or  fourth  attacks.  2  or  13.3  per  cent,  were  fatal 


CHAPTER  VIII 


PROPHYLAXIS 


The  immortal  discovery  of  Ross  is  to  the  prophylaxis  of 
malaria  what  that  of  Laveran  is  to  the  diagnosis,  and,  although 
recent,  has  already  been  instrumental  in  saving  untold  suffer- 
ing, incalculable  economic  loss,  and  thousands  of  human  lives. 

It  has  been  explained  how  the  parasite  is  abstracted  by  cer- 
tain species  of  mosquitoes  with  the  blood  of  infected  indi- 
viduals, undergoes  essential  changes  in  the  body  of  the  mos- 
quito, and  is  then  inoculated  into  healthy  persons.  It  is,  there- 
fore, evident  that  if  this  cycle  be  broken  at  any  point  infection 
cannot  occur,  and  that  if  it  were  universally  interrupted  during 
a  sufficiently  long  period  of  time  the  disease  would  be  annihi- 
lated. Hence  prophylactic  measures  may  be  directed  against 
the  destruction  of  the  malarial  parasites  within  the  body  of 
man,  the  destruction  of  the  mosquitoes  which  are  capable  of 
transmitting  the  parasites,  and  the  prevention  of  mosquitoes 
gaining  access  to  man.  The  parasite  may  be  opposed  either  in 
man  or  in  the  mosquito.  The  mosquito  may  be  combated 
either  in  its  aquatic  or  in  its  aerial  stage.  Prophylaxis  may 
be  conducted  by  a  community  or  by  an  individual,  may  be 
public  or  private,  offensive  or  defensive. 

As  is  well  known,  malaria  is  now  almost  or  entirely  absent 
from  regions  in  which  it  was  formerly  very  prevalent,  and  in 
other  places  is  rapidly  diminishing.  In  the  regions  in  mind  the 
change  was  independent  of  designed  efforts  for  the  eradication 
of  the  disease;  in  fact,  it  occurred  in  most  instances  before  the 
discovery  of  either  the  malarial  parasite  or  of  the  role  of  the 
mosquito  in  the  dissemination  of  the  disease,  and  was  an  un- 
expected result  of  the  progress  of  civilization.  This  uncon- 
scious prophylaxis  was  probably  the  product  of  several  factors, 
which  may  be  classed  as  agricultural,  therapeutic,  and  hygienic. 

302 


PROPHYLAXIS  303 

I.  Lowering  of  the  ground  water  and  consequent  diminution 
of  breeding  pools  through  drainage  for  reclamation  of  swamp 
lands,  clearing  and  cultivating  of  lands,  construction  of  levees, 
etc.  2.  More  radical  cures  of  malaria  by  means  of  cinchona 
bark  and  its  derivatives,  lessening  the  number  of  cases  of 
latent  malaria,  thereby  diminishing  the  sources  from  which 
parasites  might  be  obtained.  3.  Improved  hygienic  conditions, 
better  homes  and  food,  the  installation  of  water  and  sewerage 
systems,  improved  road  and  street  grading,  the  use  of  screens, 
mosquito  bars,  etc.  For  very  few  other  diseases  has  uncon- 
scious prophylaxis  done  so  much  as  for  malaria.  This  is  still 
exemplified  in  regions  where  malaria  is  yet  endemic;  those 
who  live  under  the  best  hygienic  conditions  suffer  least  from 
malaria,  though  they  may  even  be  ignorant  of  the  manner  of 
its  propagation. 

With  the  tediously  attained  and  in  many  cases  incomplete 
results  of  this  unconscious  prophylaxis  are  in  decided  contrast 
the  consequences  of  well  organized  and  vigorous  sanitary 
measures  directed  toward  the  prevention  of  malaria.  Many 
instances  could  be  adduced  where  within  a  comparatively  short 
space  of  time  highly  malarial  localities  have  been  almost  com- 
pletely freed  from  the  disease,  but  a  few  examples  will  suffice. 

One  of  the  most  successful  campaigns  against  malaria  was 
that  at  Ismailia,  a  town  of  about  8,000  inhabitants,  near  the 
middle  point  of  the  Suez  Canal.  The  town  was  founded  in 
1862,  and  was  celebrated  for  its  salubrity  until  1877,  when 
malaria  was  introduced  and  spread  rapidly;  in  1886  nearly 
all  the  inhabitants  were  attacked.  In  1901  the  president  of 
the  Suez  Canal  Company,  learning  something  of  the  results 
of  modern  prophylactic  methods,  dispatched  Pressat,  a  member 
of  the  medical  staff,  to  Italy  to  study  the  subject,  and  invited 
Ross  to  inspect  the  place  and  advise  upon  the  most  suitable 
manner  of  conducting  the  campaign.  In  September,  1902, 
Ross  arrived  in  company  with  MacGregor  and  with  Pressat 
returning  from  Italy.  An  abundance  of  anophelines  were 
found  in  the  houses  of  the  employes,  and  the  larvae,  especially 
in  small,  brackish  marshes,  in  the  sand,  and  in  some  of  the 
waters  of  irrigation,  but  not  in  the  main  canal,  where  they 


304  THE   STUDY   OF   MALARIA 

were  probably  destroyed  by  fish.  It  was  evident  that  mosquito 
reduction  was  to  be  the  chief  end,  though  old  cases  of  malaria 
received  vigorous  treatment.  Marshes  were  filled  with  sand 
and  the  irrigation  channels  were  deepened  or  treated  with  oil. 
This  preliminary  work  was  conducted  with  a  brigade  of  only 
four  men,  though  many  others  were  employed  later  for  the 
extensive  permanent  work.  From  1885  until  1902  inclusive 
the  number  of  cases  of  malaria  at  Ismailia  had  averaged  nearly 
1800  annually.  In  1903  there  occurred  214  cases;  in  1904. 
90,  and  in  1905  only  37.  It  is  said  that  it  is  now  possible  to 
sleep  with  comfort  in  the  place  without  nets.  The  cost  of  the 
campaign  is  estimated  at  an  initial  expenditure  of  6.25  francs, 
and  an  annual  outlay  of  2.3  francs  per  head  of  population. 

The  results  of  the  campaign  conducted  by  Travers  and  Wat- 
son at  Klang  and  Port  Swettenham,  in  the  Federated  Malay 
States,  are  hardly  less  striking.  Klang  had  3,576  inhabitants 
in  1901.  Port  Swettenham,  five  miles  away,  had  a  population 
of  about  700.  The  population  of  the  district  surrounding  the 
two  towns  was  about  14,000.  In  the  latter  part  of  1901 
malaria  was  so  extensively  prevalent  that  probably  not  more 
than  three  houses  in  Klang  escaped  infection,  and  Port  Swet- 
tenham was  being  abandoned  by  the  workmen.  .  The  antimala- 
rial campaign,  which  was  confined  to  the  towns  of  Klang  and 
Port  Swettenham,  began  in  1902.  Swamps  were  filled,  a  con- 
tour drain  established  to  intercept  incoming  water  from  sur- 
rounding springs,  and  forest  and  mangrove  trees  were  felled. 
After  the  epidemic  had  begun  to  subside  screens  were  furnished 
many  of  the  houses  and  quinine  was  distributed.  The  cost  of 
the  operations  to  the  end  of  1905  consisted  of  a  primary 
expense  of  £10,100  and  an  annual  expense  of  £410. 

The  following  table  shows  the  mortality  from  malaria  within 
the  towns  as  compared  with  that  of  the  unprotected  district : 

1900    1901   1902    1903   1904    1905 

Towns  259  368  59  46  48  45 

District  173  266  227  230  286  351 

The  most  brilliant  results  in  the  prophylaxis  of  malaria  were 
those  obtained  by  Gorgas  in  Panama,  one  of  the  most  insalu- 
brious regions  upon  the  face  of  the  earth,  having  been  called 


Fig.   75. — The  barrels  and  one  of  the  buckets  contained  many  larvae. 


Fig.    76. — Anopheles    larvae    in    the  barrel.     A  fatal   case  of   comatose  malaria 
occurred  here  a  few  weeks  before  the  picture  was  taken. 


Fig.   77. — Unmindful  of  the  danger  lurking  in  the  barrel. 


Fig.   78. — Fire   barrels  containing  larvse. 


Fig.    79. — Water   barrels  may   prevent  the   spread  of  fire,   but   will  breed  mos- 
quitoes unless  covered. 


Fig.  80. — Stock  pond  containing  anopheles  larvae.     Too  near  the  dwelling. 


Fig.  81. — A  protected  pool  in  a  lumber-yard  containing  myriads  of   anopheles 

larvae. 


Fig.  82. — A   typical  "  bayou,"  the  headquarters  of  malaria. 


Fig.  83. — An  ill-chosen  town  site  along  the  bayou. 


PROPHYLAXIS  305 

during  French  occupation  "the  Frenchman's  Grace."  It  is  a 
common  report  that  in  the  railroad  between  Panama  and  Colon 
every  cross-tie  represents  the  corpse  of  a  laborer. 

The  canal  zone  is  fifty  miles  in  length,  with  Panama  and 
Colon  at  each  end.  The  average  number  of  employes  is  40,000. 
The  efforts  consisted  in  the  destruction  of  breeding  places  only 
within  200  yards  of  the  camps  and  villages,  no  attempts  being 
made  to  deal  with  those  farther  off.  All  the  houses  were 
screened  and  the  people  were  urged  to  use  mosquito  bars. 
Quinine  was  furnished  them  and  they  were  advised  to  take  3 
grains  daily.  The  abolition  of  the  breeding  pools  was  regarded 
as  a  most  important  measure.  Owing  to  the  heavy  rainfall  and 
the  luxuriant  vegetation  the  ditches  filled  rapidly  with  grass, 
and  it  was  found  much  cheaper  to  concrete  them.  Subsoiling 
by  means  of  the  tile  drain  covered  with  rock  and  soil  was  used 
wherever  possible. 

The  result  is  that  the  death  rate  has  been  lowered  until  it 
does  not  exceed  that  of  New  York  City. 

I.    MEASURES  DIRECTED  FOR  THE  DESTRUCTION  OF 
MOSQUITOES 

Destruction  of  breeding  pools  for  the  anopheles  is  an  effi- 
cient preventive  measure.  It  is  chiefly  through  the  eradication 
of  breeding  places  that  so-called  unconscious  prophylaxis  has 
accomplished  its  results.  This  method  has  received  the  chief 
consideration  in  the  greatest  antimalarial  campaigns.  It  is 
more  permanent  and  possesses  the  further  advantage  in  many 
instances  of  being  cheaper  in  the  end. 

It  is  neither  necessary  nor  in  every  case  advisable  to  remove 
the  surface  water  from  the  whole  of  a  malarial  country,  but 
only  in  the  region  of  habitations  or  where  anopheles  are  known 
to  breed.  In  the  Panama  campaign  the  area  of  destruction 
extended  only  200  yards  from  camps  and  habitations.  This 
should  probably  be  the  minimum  radius,  though  work  at  a 
much  greater  distance  is  only  a  useless  expense. 

In  the  area  to  be  protected  the  land  should  be  cleared  of 
weeds,  undergrowth,  bushes,  and  unnecessary  trees  to  pro- 
mote evaporation  and  prevent  the  formation  of  puddles. 
20 


306  THE    STUDY    OF   MALARIA 

Grocery  cans,  broken  bottles,  buckets,  and  old  tinware  which 
might  retain  water  should  best  be  buried.  Water-barrels,  tanks, 
cisterns,  and  wells  should  be  emptied,  filled,  or  screened.  Gut- 
ters should  be  maintained  in  such  a  condition  that  water  cannot 
accumulate. 

The  stock  pond,  so  common  in  the  vicinity  of  habitations  in 
some  sections,  is  a  menace  to  both  man  and  beast  and  should 
not  be  tolerated. 

The  care  of  streams  and  large  bodies  of  water  is  ordinarily 
simple,  since  these  rarely  threaten  sanitation  as  anopheles 
breeders.  Within  the  protected  area  the  banks  should  be 
cleared  of  dense  weeds  and  bushes,  eddies  prevented  where 
possible,  and  pools  along  the  edges  drained  into  the  channel. 

In  the  case  of  streams  that  get  very  low  after  the  rainy 
season,  leaving  a  chain  of  pools  along  the  river-bed,  these  pools 
should  be  drained  into  each  other  and  an  attempt  made  to 
reestablish  a  flow  and  to  permit  of  scouring  and  the  access  of 
fish  from  the  larger  pools.  Where  the  pools  are  small  much 
water  can  be  gotten  rid  of  by  the  use  of  brooms. 

In  the  case  of  large  bodies  of  water  subject  to  overflow  the 
problem  is  more  difficult.  The  primary  effect  of  the  submerg- 
ing of  land,  while  the  water  is  high,  is  to  diminish  malaria. 
The  secondary  effect,  after  the  waters  have  receded,  is  to 
cause  a  marked  increase.  A  remarkable  example  which  illus- 
trates this  occurred  in  Holland  in  1748.  The  Dutch  allowed 
the  land,  for  defensive  purposes,  to  become  overflowed.  Peace 
being  concluded  during  the  middle  of  the  summer,  the  inunda- 
tion was  caused  to  subside,  whereupon  a  serious  outbreak  of 
malaria  occurred.  The  epidemic  was  not  successfully  com- 
bated until  the  land  was  again  submerged  and  kept  so  until 
the  advent  of  winter.  The  effect  upon  malaria  of  inundations 
is  almost  yearly  observed  in  the  valleys  of  the  Nile,  of  the 
Mississippi,  and  of  other  large  streams.  Levees,  dykes,  and 
other  engineering  means  of  large  dimensions  are  the  only 
remedies;  these  being  expensive  are  rarely  employed  merely 
for  sanitary  purposes. 

Marshes  and  swamps  when  too  extensive  to  be  filled  may 
be  effectively  drained.     The  drains  should  be  narrow,  of  suffi- 


Fig.  84. — Anopheles  breed  among  the  cypress    knees. 


Fig-  85- — Many  breeding-places  are   left    upon  the  lowlands  after  the  overflow 

has  receded. 


Fig.    86. — A    stranded    skiff    containing    a    little    water    and    many    anopheles 

wrigglers. 


Fig    88. — This  pool,  fed  from  the  ice-plant,  contained   larvae  weeks  after  most 
other  pools  had  disappeared. 


Fig.   89. — Hunting  for  anopheles  larvae  along  the  leve'e. 


Fig.  90. — An  embrvc   scientist  searching  for  anopheles   larvae. 


Fig.  91. — Breeding  pools  in  the  borrow  pits  along  a  railroad. 


Fig.  92. — Breeding  pools  along  the  roadside. 


PROPHYLAXIS  307 

cient  depth  and  fall  to  drain  effectively,  and  may  be  parallel, 
crowfoot  fashion  or  otherwise,  as  best  suited  to  local  condi- 
tions. If  concreted  they  require  less  after-treatment  and  may 
be  cheaper  in  the  end.  If  not  concreted  they  should  be  fre- 
quently inspected  to  prevent  caving,  deposit,  or  filling  with 
vegetation.     Tile-drains  are  usually  very  efficient. 

Large  swamps  in  the  vicinity  of  streams  have  been  rendered 
unfit  as  breeding  places  by  directing  the  course  of  the  stream 
through  them.  The  water  is  thus  given  a  current,  and  if  the 
stream  contains  much  mud  in  suspension  the  bed  of  the  marsh 
is  gradually  filled. 

Fresh-water  ponds  close  to  the  sea  have  been  successfully 
treated  by  filling  with  salt  water.  It  is  said  that  a  large  fresh- 
water lake  back  of  the  hotels  at  Virginia  Beach  which  bred 
numerous  mosquitoes  was  filled  with  salt  water  by  means  of 
machinery  with  a  satisfactory  result.  Water  strong  in  salt  is 
not  attractive  for  breeding  purposes,  though  brackish  water 
may  harbor  numerous  larvae. 

The  rendering  innocuous  of  borrow  pits  along  railroad  lines 
(Fig.  91)  is  difficult.  It  is  much  easier  to  prevent  the  stagna- 
tion of  water  during  the  construction  of  the  road  than  it  is 
to  remedy  the  defect  after  completion.  Filling  and  drainage 
are  the  best  correctives.  It  should  be  the  duty  of  some  one 
to  see  that  the  construction  of  railroads,  canals,  and  similar 
enterprises  does  not  render  a  country  more  unsanitary. 

The  destruction  of  smaller  pools  and  puddles  is  usually 
simple  and  goes  far  toward  prophylaxis,  since  it  is  in  such 
places  that  anopheline  mosquitoes  breed  by  preference.  Filling 
is  by  far  the  most  permanent,  hence  the  cheapest  and  most 
desirable  method  by  which  to  deal  with  these  collections  of 
water.  Pools  in  ditches  along  the  sides  of  roads  (Fig.  92), 
wheel  ruts,  hoofprints  of  stock  in  soft  ground,  water  remain- 
ing in  natural  inequalities  in  the  ground  and  in  excavations 
for  various  purposes  should  be  assiduously  attended.  The 
work  should  be  conducted  by  one  who  is  familiar  with  the 
rudimentary  principles  of  drainage.  The  organization  for  this 
purpose  of  "mosquito  brigades"  was  first  suggested  and  put 
into  practice  by  Ross,392  whose  advice  is  as  follows :  "Attack 


308  THE    STUDY   OF   MALARIA 

first  those  collections  of  water  the  obliteration  of  which  will 
remove  the  largest  number  of  mosquitoes  for  the  least  amount 
of  money.  Thus  it  is  quite  useless  to  drain  stagnant  water 
simply  because  it  is  stagnant  water.  The  superintendent  should 
first  assure  himself  that  it  does  actually  contain  larvae,  and, 
better,  that  it  constantly  contains  them.  As  already  mentioned, 
some  pools  are  too  large,  others  are  too  small,  and  others  are 
subject  to  scouring,  and,  though  these  conditions  often  change 
at  certain  seasons,  when,  for  instance,  large  pools  dry  up,  yet 
some  pools  appear  to  be  habitually  unsuited  to  the  larvae.  It 
is  useless  to  spend  much  money  over  these.  Again,  it  is  not 
advisable  to  attack  without  discrimination  even  the  pools  which 
do  contain  larvae.  Some  contain  many  more  larvae  than  others 
do;  and,  in  my  experience,  while  larvae  do  occur  in  some  con- 
siderable bodies  of  water,  such  as  marshes  or  ponds,  they  are 
generally  much  more  numerous  in  small  pools.  Now,  it  is 
evidently  bad  economy  to  spend  large  sums  over  draining  large 
bodies  of  water  when  small  puddles,  easily  dealt  with,  really 
cause  more  mischief.  The  superintendent  must  suppose  noth- 
ing— he  must  never  suppose  because  a  marsh  exists  in  a  neigh- 
borhood that  it  is  the  only  or  the  principal  cause  of  malaria. 
He  must  study  the  point  by  careful  search  for  anopheles 
larvae ;  and  may  often  find  that  a  small,  unobserved  pool  in  the 
street  is  more  dangerous  than  a  marsh  a  mile  away. 

The  number  and  nature  of  the  breeding  pools  depend  so 
much  upon  the  configuration  of  the  ground,  the  character  of 
the  soil,  and  the  amount  of  the  rainfall  that  it  is  impossible  to 
give  very  minute  directions  regarding  the  method  of  dealing 
with  them.  The  superintendent  must  be  guided  by  his  own 
judgment,  remembering  only  the  maxim,  which  applies  to  most 
kinds  of  work,  "The  simplest  measures  first." 

The  height  of  the  ground  water  is  very  intimately  associated 
with  the  prevalence  of  malaria,  since  the  quantity  of  surface 
water  depends  largely  upon  the  height  of  the  ground  water,  and 
the  latter,  when  appearing  upon  the  surface,  is  a  favorite 
breeding  site  for  malarial  mosquitoes.  Hence,  measures 
directed  toward  the  lowering  of  the  ground  water  are  of  the 
highest  efficacy  in  the  prophylaxis  of  malaria.     This  is  evi- 


Fig.  93. — Breeding  pools  on  a  rice  farm. 


PROPHYLAXIS  309 

denced  by  the  results  of  the  "tiling"  of  land  and  by  the  forma- 
tion of  drainage  districts  for  the  reclamation  of  swamp  lands. 
Such  procedures  often  render  unnecessary  the  expenditure  of 
labor  or  money  for  the  removal  of  breeding  pools  or  other  anti- 
larval  steps. 

Ground  water  is  lowered  by  various  methods,  the  most 
primitive  of  which  is  ditching.  These  ditches  are  left  open 
or  are  partly  filled  with  gravel  or  stone,  then  with  earth.  The 
unglazed  tile  drain  is  very  effective;  perforated  drains  have 
been  employed  also. 

In  certain  regions  where  the  hardpan  or  impervious  stratum 
is  responsible  for  a  high-ground  water  excellent  results  have 
been  obtained  by  boring  through  this,  thereby  allowing  the 
water  to  escape  into  the  permeable  earth  beneath.  These  are 
the  so-called  absorbing  wells. 

It  is  well  known  that  rice  culture  increases  the  malaria  of  a 
region  to  a  great  extent  (Fig.  93).  In  some  of  the  Oriental 
countries  the  crop  is  a  necessity,  but  in  regions  not  absolutely 
dependent  upon  the  crop  the  cultivation  of  rice  must  be  looked 
upon  as  an  evil.  In  fact,  some  governments  have  either  thrown 
certain  restrictions  around  the  industry  or  have  altogether 
prohibited  it. 

Since  the  time  of  Pliny  it  has  been  the  theory  that  trees 
render  a  locality  more  salubrious  by  filtering  out  miasmatic 
exhalations.  The  eucalyptus  globulus  has  attained  considerable 
reputation  in  this  respect,  probably  from  a  belief  that  it  absorbs 
moisture  from  the  soil  and  renders  it  drier.  Recent  experi- 
ments in  Italy  have,  however,  shown  that  this  tree  has  no 
effect  in  decreasing  malaria,  and  that  it  even  affords  an  excel- 
lent shelter  for  anopheles  mosquitoes. 

Sunflowers  and  castor-oil  plants,  which  are  reputed  to  be 
beneficial  in  the  prophylaxis  of  malaria,  are  probably  devoid  of 
such  virtue. 

There  are  circumstances  under  which  it  is  impossible  to 
destroy  the  breeding  pools.  Here  the  use  of  petroleum  is  indi- 
cated. This  oil  is  also  useful  in  antimalarial  campaigns  as 
a  temporary  measure  in  part  of  the  work  while  permanent 
means  are  being  employed  elsewhere. 


3IO  THE    STUDY    OF   MALARIA 

While  the  value  of  petroleum  as  a  larvicide  was  known  early 
in  the  nineteenth  century,  to  Howard  belongs  the  credit  of  its 
practical  application. 

An  oil  should  be  chosen  which  spreads  rapidly  and  evapo- 
rates slowly.  The  refined  illuminating  oil  evaporates  readily, 
hence  is  too  expensive  for  work  on  a  large  scale.  The  most 
suitable  is  the  fuel  oil  or  blast-furnace  oil.  The  oil,  forming 
a  film  upon  the  entire  surface  of  the  water,  chokes  the  air. 
tubes  of  the  larvae,  which  come  to  the  surface  to  breathe. 
The  pupae  expire  even  earlier  than  the  larvae,  since  they  require 
more  air.  Furthermore,  not  a  few  adult  female  mosquitoes  in 
the  act  of  oviposition  are  thereby  destroyed.    . 

The  pool  should  be  cleared,  as  far  as  possible,  from  weeds 
and  algae  which  interfere  with  the  spread  of  the  oil.  The  oil 
should  be  poured  from  a  watering  pot,  sprayed  by  means  of  a 
force  pump,  or  painted  over  the  surface  with  saturated  cloths 
tied  to  the  ends  of  sticks.  An  automatic  oiler  may  be  impro- 
vised by  placing  a  barrel  of  oil  a  few  feet  above  the  water  to 
give  the  oil  the  necessary  spread,  and  having  a  perforation  in 
the  bottom  of  the  barrel  to  drop  about  twenty  times  to  the 
minute. 

The  quantity  of  oil  which  has  been  found  amply  sufficient 
is  i  ounce  for  each  15  square  feet  of  surface.  It  has  been  esti- 
mated that  a  barrel  of  oil  costing  only  a  few  dollars  is  suffi- 
cient to  cover  96,000  square  feet  of  surface. 

Evaporation,  rains,  and  winds  prevent  permanent  results,  so 
that  the  oiling  must  be  repeated.  Intervals  of  two  or  three 
weeks  are  the  proper  average,  and  certain  days  of  the  month 
should  be  systematically  chosen.  .  It  is  best  to  begin  the  oiling 
in  the  spring  to  prevent  the  first  generations. 

Nearly  every  antiseptic  and  poison  has  been  employed  for 
the  destruction  of  mosquito  larvae.  The  aniline  derivatives 
are  valuable,  especially  that  known  as  Larvicide,  which  destroys 
also  fish  and  other  forms  of  life  which  may  be  useful  in  killing 
larvae.  The  same  objection  applies  to  Phinotas  Oil,  a  cresol 
combination,  and  saprol,  which  are  effective  larvicides.  Forma- 
lin, corrosive  sublimate,  carbolic  acid,  and  lysol  are  too  slow 
in  their  effects  upon  larvae  to  be  of  practical  value.     Perman- 


PROPHYLAXIS  311 

ganate  of  potash  has  proved  disappointing  in  all  trials  made 
of  it.  Tar,  creosote,  tobacco,  pyrethrum,  sulphate  of  iron,  and 
numerous  other  substances  have  been  used  and  abandoned. 
Nothing  is  so  efficacious,  so  free  from  danger,  and  so  inexpen- 
sive as  kerosene. 

Where  it  is  not  feasible  either  to  drain  or  oil  a  breeding  pool 
the  introduction  of  small  fish  has  been  practised  with  success. 
Certain  species  of  fish  prey  upon  the  eggs,  larvae,  and  pupae 
of  mosquitoes,  and  even  upon  adults  when  about  to  emerge 
from  the  pupal  shell  or  when  in  the  act  of  oviposition.  The 
common  top  minnows  (Gambusia  and  Funduhis)  and  the  sun- 
fish  are  excellent  for  this  purpose.  The  former  being  very 
voracious  and  top-feeders,  are  especially  adapted  for  the  de- 
struction of  anopheles  larvae.  They  are  fast  breeders  and 
resist  the  drying  of  pools  in  a  remarkable  degree.  Sticklebacks, 
gold-fish,  and  roach  are  also  larvivorous.  It  is  doubtful 
whether  the  common  German  carp,  on  account  of  its  feeding 
habits,  is  of  any  use  for  this  purpose.  The  tadpole  is  valueless 
for  the  destruction  of  larvae. 

The  larvae  of  dragon-flies  devour  the  mosquito  larvae  among 
other  prey.  Feeding  upon  the  bottom,  however,  they  are  not 
very  effective,  as  to  anopheles  larvae  especially,  unless  the  pool 
be  shallow,  in  which  case  they  may  destroy  great  numbers. 

The  water  boatman  (notonectidw)  is  an  efficient  enemy,  and 
many  mosquito  larvae  are  cannibalistic  among  the  smaller 
forms,  even  of  the  same  species. 

The  hair  worm,  a  species  of  mermis,  is  sometimes  a  fatal 
parasite  of  mosquito  larvae.  During  a  certain  summer  Stiles114 
found  that  many  of  the  larvae  which  he  collected  died  in  the 
laboratory.  Upon  dissection  he  found  them  infested  with  the 
hair  worm.  It  was  noted  that  in  years  when  mosquitoes  were 
scarce  this  parasite  was  plentiful. 

Giles119  in  India  found  larvae  infested  by  a  parasitic  stalked 
infusorian,  and  suspects  that  they  may  be  the  cause  of  the 
inexplicable  disappearance  of  larvae  from  places  where  they 
were  formerly  abundant. 

Galli-Valerio  and  de  Jongh82  observed  from  laboratory  and 
field  experiments  that  aspergillns  niger  and  glaucus,  especially 


312  THE   STUDY   OF   MALARIA 

the  former,  exercised  a  very  unfavorable  influence  upon  the 
development  of  mosquito  larvae. 

The  cultivation  of  the  water  pest  (anacharis  alsinastrum) , 
which  so  thickly  covers  the  surface  of  the  water  as  to  prevent 
the  larvae  and  pupae  from  gaining  access  to  the  air,  has  been 
recommended  as  a  prophylactic  measure.  It  is  said  that  in 
certain  localities  the  disappearance  of  malaria  coincides  chrono- 
logically with  the  appearance  of  the  water  pest. 

The  natural  enemies  of  adult  mosquitoes  are  few  and  prac- 
tically insignificant.  Dragon-flies,  night-hawks,  whip-poor- 
wills,  swallows,  bats,  and  certain  species  of  lizards  destroy  a 
number  and  some  are  killed  by  parasitic  mites  and  a  small 
suctorial  fly. 

An  ideal  prophylaxis  destroys  the  breeding  pools  or  the 
aquatic  stages  of  mosquitoes,  but  remedies  against  the  adult 
insects  are  sometimes  necessary.  For  this  purpose  a  great 
variety  of  substances  has  been  tried.  One  of  the  most  primitive 
of  measures  is  the  smoldering  fire  of  chips,  rags,  and  feathers, 
to  be  seen  in  summer  twilight  to  the  windward  of  nearly  every 
negro  cabin. 

The  most  practical  means  are  the  fumes  of  burning  sulphur 
and  of  pyrethrum  powder.  The  room  to  be  fumigated  should 
be  made  as  nearly  airtight  as  possible. 

Of  sulphur,  from  2  to  5  pounds  should  be  used  for  every 
1,000  cubic  feet  of  space.  Its  deleterious  effect  upon  metals 
and  delicate  fabrics  limits  its  use  somewhat.  Sulphur  dioxide 
fumes  have  been  found  to  be  an  excellent  insecticide.  Rose- 
nau393  says  of  it :  "Very  diluted  atmospheres  of  the  gas  will 
quickly  kill  mosquitoes.  It  is  as  efficacious  for  this  purpose 
when  dry  as  when  moist,  whereas  the  dry  gas  has  practically  no 
power  against  bacteria.  Contrary  to  formaldehyde,  it  has  sur- 
prising powers  of  penetrating  through  clothing  and  fabrics, 
killing  the  mosquitoes  even  when  hidden  under  four  layers 
of  toweling,  in  one  hour's  time,  and  in  very  diluted  proportions. 
This  substance,  which  has  been  so  long  disparaged  as  a  disin- 
fectant because  it  fails  to  kill  spores,  must  now  be  considered 
as  holding  first  rank  in  disinfection  against  yellow  fever, 
malaria,  filariasis,  and  other  insect-borne  diseases." 


PROPHYLAXIS 


3*3 


The  room  should  be  kept  closed  for  several  hours  to  insure 
the  complete  extermination  of  the  insects. 

Pyrethrum  powder  may  be  burned  in  the  proportion  of  a 
few  ounces  to  a  pound  for  each  1,000  cubic  feet  of  space.  It 
may  be  moistened  with  water,  molded  into  cones,  and  dried, 
or  the  powder  may  be  slightly  dampened  at  the  summit  with 
alcohol  and  lighted.  The  mosquitoes  are  suffocated  by  the 
fumes  and  must  be  swept  up  and  destroyed. 

Formaldehyde  has  been  tried  and  found  wanting,  but  may  be 
effective  when  very  large  quantities  are  rapidly  liberated  in 
a  tight  room  with  few  hiding  places  for  the  insects. 

The  pulverized  leaves  and  stems  of  the  common  jimson 
weed  (Datura  stramonium) ,  mixed  with  saltpeter,  and  burned 
in  the  proportion  of  5  ounces  to  1,000  cubic  feet  of  space,  have 
been  successfully  used  by  the  New  Jersey  Mosquito  Commis- 
sion. 

Chlorine  gas,  generated  by  adding  a  few  drams  of  sulphuric 
acid  to  an  ounce  of  chloride  of  lime,  is  said  to  be  efficient,  and 
burning  tobacco  leaves  are  useful. 

The  following  table  copied  from  Celli80  shows  the  effects 
of  various  odors,  fumes,  and  gases  upon  adult  mosquitoes 
according  to  his  experiments  : 

Action  of  culicidal  substances  on  mosquitoes  (C.  annulatus, 
C.  pip  pens,  A.  claviger)  : 


I.  Odors 

„  .                      ,  Time  in  which  death  is  manifested. 

No.                                      Substances  used.  .  .         , 

Apparent.  Actual. 

1.  Essential  oil  of  turpentine 1  min.  1  min. 

2.  Iodoform    10  min.  40  min. 

3.  Menthol   10  min.  45  min. 

4.  Nutmeg    10  min.  2  hours 

5.  Musk    30  min.  3  hours 

6.  Camphor   4-5  min  4-5  hours 

7.  Leek   5-10  min.  5  hours 

8.  Crushed    pepper 20  min.  6  hours 

9.  Naphthalene   10-35  min.  8  hours 

10.  Roman    wormwood 6  hours  24  hours 

11.  Onion   4-6  hours  Survive 

12.  Salvia Survive 

13.  Rosemary Survive 

14.  Dry  and  fresh  basil Survive 

15.  Cinnamon   bark Survive 

16.  Asafetida    Survive 


3^4 


THE   STUDY   OF   MALARIA 


II.  Fumes 

Time  in  which  death  is  manifested. 
Substances  used.  Apparent.  Actual. 

i.  Tobacco   Instantly  1-3  min. 

2.  Larvicide  Instantly  5  min. 

3.  Chrysanthemum      powder       (unexpanded 

flowers)     5  min.  1  hour 

4.  Valerian    root 5  min.  2  hours 

5.  Fresh  leaves  of  eucalyptus 3-5  min.  3  hours 

6.  Quassia  wood 16  min.  5  hours 

7.  Pyrethrum   powder 5  min.  6  hours 

8.  Dry  leaves  of  Mentha  pulegium 5  min.  8  hours 

9.  Pitch    10-13  min.  8  hours 

10.  Dry  leaves  of  basil 2-6  min.  24  hours 

11.  Dry  rosemary  7-12  min.  24  hours 

12.  Culicidal    cones 2-10  min.  36  hours 

13.  Dry  chamomile  flowers 2-10  min.  36  hours 

14.  Dry  leaves  of  Saturgia  hortensis 2-10  min.  36  hours 

15.  Salvia  leaves 8-10  min.  36  hours 

16.  Wood   5-7  min.  12-48  hours 

17.  Guaiacum    resin 12  min.  Survive 

18.  Myrrh    15  min.  Survive 

19.  Elemi    15  min.  Survive 

20.  Incense    15  min.  Survive 

III.  Gases 

Time  in  which  death  is  manifested. 
Substances  used.  Apparent.  Actual. 

1.  Sulphur    dioxide    Instantly  1  min. 

2.  Hydrogen    sulphide    Instantly  1  min. 

3.  Ammonia    1  min.  2  min. 

4.  Illuminating  gas  1  min.  2  min. 

5.  Formaldehyde   (Trillat's  apparatus) 2  min.  10-15  min. 

6.  Sulphuret  of  carbon 15-30  min.  Survive 

7.  Acetylene    ...  Survive 

Ross'392  summary  is  a  fitting  conclusion  to  the  consideration 
of  mosquito  destruction : 

Summary  of  Objects 

1.  We  do  not  propose  to  exterminate  mosquitoes  in  any- 
entire  continent.  We  propose  only  to  deal  with  them  in  the 
town  in  which  we  live  and  in  its  suburbs. 

2.  We  do  not  propose  to  get  rid  of  every  mosquito  even  in 
this  town.  We  aim  only  at  reducing  the  number  of  the  in- 
sects as  much  as  possible. 

3.  We  do  not  think  it  possible  to  drain  or  otherwise  treat 
every  breeding  place  in  the  town.  We  aim  at  dealing  with 
as  many  as  possible. 

4.  We  cannot  exclude  mosquitoes  which  may  just  possibly 
be  blown  into  the  town  from  miles  away.  We  content  our- 
selves with  preventing  the  insects  breeding  in  the  town  itself. 


prophylaxis  315 

Summary  of  Methods 

1.  We  start  work  at  once  with  whatever  means  we  can 
scrape  together. 

2.  We  operate  from  a  center  outward. 

3.  We  clear  houses,  backyards,  and  gardens  of  all  rubbish, 
empty  tubs  and  cisterns  containing  larvae,  or  destroy  the  larvae 
in  them  by  means  of  oil. 

4.  We  show  people  how  to  do  these  things  for  themselves, 
and  how  to  protect  tubs  and  cisterns  by  means  of  wire  gauze. 

5.  When  we  have  cleared  as  many  houses  as  we  determine 
to  deal  with  we  clear  them  over  and  over  again. 

6.  We  fill  up  or  drain  away  all  the  pools,  ditches,  old  wells, 
and  puddles  we  can — especially  those  which  contain  most 
larvae. 

7.  Such  pools  as  cannot  be  filled  up  or  drained  are  deepened 
and  cleared  of  weeds  if  they  contain  larvae. 

8.  Streams  and  water-courses  which  possess  larvae  are 
"trained." 

9.  Where  we  can  do  nothing  else  we  destroy  larvae  period- 
ically with  oil,  or  by  brushing  them  out  with  brooms,  or  by 
other  means. 

10.  We  endeavor  to  interest  our  neighbors  in  the  work,  and 
to  educate  the  town  into  maintaining  a  special  gang  of  men 
for  the  purpose  of  keeping  the  streets  and  gardens  absolutely 
free  of  stagnant  mosquito-bearing  water. 

Motto  : 

Our  motto  should  be  one  which,  I  think,  will  shortly  become 
the  first  law  of  tropic  sanitation,  namely : 

"NO  STAGNANT  WATER." 

II.    MEASURES  DIRECTED  TOWARD  THE  DESTRUCTION  OF 

PARASITES 

Efforts  to  destroy  the  malarial  parasites  in  the  human  body 
assume  two  modes.  The  first  consists  of  the  radical  cure  of 
the  malaria-infected  individual,  the  prevention  of  a  relapse, 
thereby  benefiting  the  individual  and  annihilating  a  source  of 


316  THE   STUDY  OF   MALARIA 

danger  to  the  community.  The  second  mode  consists  of  the 
administration,  to  persons  not  necessarily  infected,  of  a  drug 
which  destroys  the  parasite  soon  after  the  latter  is  introduced 
into  the  body,  before  the  incubative  stage  is  completed. 

Cases  of  latent  and  atypic  malaria  (Fig.  94)  are  of  greater 
importance  to  prophylaxis,  being  sources  of  greater  danger  to 
communities  than  are  typic  acute  cases.  The  duration  of  the 
acute  attack  is  short,  the  patient  is  apt  to  be  placed  under  rela- 
tively favorable  conditions  and  to  receive  quinine;  he  does 
not  wander  and  disseminate  the  disease,  and  his  blood  may 
contain  but  few  sexual  forms  of  the  parasite.  On  the  other 
hand,  the  subject  of  latent  malaria  may  harbor  parasites  for 
months,  and,  the  condition  being  unrecognized  or  ignored,  he 
does  not  take  quinine,  and  is  a  fountain  of  infection  in  diverse 
places  and  for  prolonged  periods. 

Koch  has  maintained  that  the  prompt  and  permanent  cure 
of  all  acute  cases  of  malaria  and  the  systematic  search  for,  and 
appropriate  treatment  of,  all  latent  cases  in  a  region  will  result 
in  the  extermination  of  the  disease  from  such  a  locality.  This 
is  theoretically  possible,  but  could  be  practised  only  in  small 
communities  under  perfect  control.  Nevertheless,  it  is  cer- 
tainly the  duty  of  physicians  to  endeavor  to  effect  radical  cures 
of  the  cases  which  come  under  their  observation,  a  duty  owed 
not  only  to  the  patient,  but  to  the  public,  and  such  efforts  will 
go  far  toward  the  eradication  of  the  disease. 

Quinine  Prophylaxis. — Theoretically  the  administration  of 
quinine  to  healthy  individuals  for  the  prevention  of  malaria  is 
not  an  ideal  method  of  prophylaxis,  for,  strictly  speaking,  it 
does  not  prevent  infection,  but  destroys  the  parasites  in  the 
incubative  stage  after  inoculation  into  the  human  body.  But 
no  one  method  satisfies  all  conditions ;  each  has  its  advantages 
and  its  limitations,  and  frequently  two  or  more  methods  must 
be  employed  simultaneously. 

Quinine  prophylaxis  is  indicated  in  proportion  to  the  diffi- 
culty of  pursuing  more  permanent  methods.  It  is  valuable 
where  screens  and  bars  are  not  available,  as  in  camping, 
marching,  traveling,  or  where  the  occupation  takes  one  out  at 
night.    When  residents  of  non-malarial  countries  go  into  mala- 


Fig.  94. — Carriers  of  latent  infections  are  disseminators  of  the  disease. 


PROPHYLAXIS  317 

rial  localities,  especially  in  the  rural  districts,  for  short  spaces 
of  time  quinine  is  a  most  valuable  prophylactic.  After  infec- 
tion is  known  to  have  occurred  quinine  is,  of  course,  essential 
not  only  as  a  cure,  but  as  a  preventive.  It  may  be  employed 
effectively  where  it  is  impossible  to  destroy  mosquitoes  or  as 
an  adjunct  to  other  measures. 

Numerous  experiences  attest  the  value  of  quinine  in  the 
prophylaxis  of  malaria. 

The  observations  of  Logan,394  made  upon  soldiers  of  the 
Civil  War,  were  as  follows :  Of  230  men  who  took  no  quinine 
134  had  fever,  a  ratio  per  1,000  of  582.  Of  246  men  who  took 
quinine  irregularly  96  had  fever,  a  ratio  per  1,000  of  390.  Of 
506  men  who  took  quinine  regularly  98  had  fever,  a  ratio  of 
193  per  1,000. 

Jilek86  reports  that  among  736  soldiers,  living  under  similar 
conditions,  5,000  took  0.10  gram  of  sulphate  of  quinine  each 
morning  and  only  18  per  cent,  had  fever,  which  was  mild  and 
recurrences  few.  Among  the  236  men  who  took  no  quinine 
28  per  cent,  had  fever. 

At  Melaboe,  in  the  Dutch  Indies,  there  were,  during  1896, 
in  the  garrison  1,237  days  of  sickness  and  33  men  excused 
for  malaria;  in  1897,  1,841  days  of  sickness  and  44  cases  of 
malaria.  Beginning  with  November,  1907,  each  soldier  took 
0.50  gram  of  quinine  twice  a  week.  During  1908  there  were 
only  214  days  of  sickness  and  no  one  dismissed  on  account  of 
malaria.1 

At  the  prison  of  Bhagalpur  the  average  mortality  had  been 
48  per  1,000.  With  cinchonidine  prophylaxis  it  fell  to  9  per 
1,000  in  1895,  and  to  7.2  per  1,000  in  1896.  The  civil  popula- 
tion suffered  heavily  from  malaria  during  this  time.1 

During  1901  the  malarial  morbidity  in  the  Grossetane  marsh, 
which  was  formerly  55  per  cent.,  was  reduced  to  24.53  Per 
cent. 

In  Italy,  Mori79  gave  to  persons  over  sixteen  years  of  age 
0.50  gram  euquinine  daily,  and  to  children  0.25  gram,  with  the 
result  that  of  these  only  6.25  per  cent,  were  attacked,  while  of 
those  who  took  no  prophylactic  81  per  cent,  took  the  disease. 

Ziemann48  observed  in  Cameroon  that  among  25  persons  who 


318  THE   STUDY   OF  MALARIA 

did  not  use  quinine  all  were  attacked  with  malaria,  with  a 
mortality  of  36  per  cent.  Of  69  who  used  quinine  regularly- 
according  to  his  method  16  per  cent,  remained  free  from  mala- 
ria, and  among  those  attacked  only  4.35  per  cent.  died. 

Babes395  employed  Koch's  method  of  quinine  prophylaxis  in 
Roumania.  In  one  locality  of  214  inhabitants  who  took  quinine 
prophylactically  no  case  of  malaria  occurred,  while  among  32 
who  used  no  preventive  there  were  15  cases.  In  another  local- 
ity, in  which  1,800  inhabitants  were  thus  treated,  not  a  single 
case  occurred,  though  in  800  who  did  not  employ  the  prophy- 
lactic the  morbidity  was  20  per  cent. 

During  a  severe  epidemic  in  1907  in  Marathon,  a  highly 
malarial  locality,  Hadjimichalis  and  Cardamatis93  had  the  fol- 
lowing experience  with  Koch's  method : 

Of  67  persons  who  took  quinine  for  21-24  weeks  none  were 
infected;  of  145  who  took  it  for  16-20  weeks  20.6  per  cent, 
were  attacked;  of  220  who  took  the  drug  for  11-16  weeks  48.6 
per  cent,  were  attacked;  of  820  who  took  it  for  1-10  weeks 
56.5  per  cent,  were  infected. 

The  following  table  shows  the  effect  of  quinine  prophylaxis 
in  the  community  of  Stroppiana  :83 

v  Cases  of  Grams  of  Quinine 

*ear-  Malaria.  Consumed. 

1903  87  800 

1904  57  2500 

1905  44  4025 

1906  26  5832 

1907  II  4500 

The  Society  for  the  Study  of  Malaria  in  Italy,  beginning 
prophylactic  experiments  on  a  small  scale  in  limited  areas,  have 
extended  their  practical  efforts  until  the  results  are  felt 
throughout  the  entire  country. 

Quinine  has  been  the  chief  reliance  of  this  organization. 

The  following  figures  give  the  malarial  mortality  in  Italy 
from  1900  to  1907 : 

Year.  Deaths.  Year.  Deaths. 

1900  15,865      1904  8,463 

1901  I3>558      1905  7,845 

1902  9,908      1906  4,871 

1903  8,517      1907  4,l60 


PROPHYLAXIS  319 

Malarial  admissions  to  the  hospital  of  Marcianise : 

Year.  Cases.  Year.  Cases. 

1900  6oi      1904  138 

1901  4!0      1905  I24 


Cases. 

Year. 

601 

1904 

410 
227 
126 

1905 
1906 
1907 

112 


1902  

1903  126     1907  47 

The  distribution  of  quinine  by  the  Italian  Government  has 
had  a  decided  effect  upon  the  prevalence  of  malaria,  as  evi- 
denced by  the  following: 

Number  of  Morbidity. 

Year.  persons. 

1902  3,055  7-7 

1903  19,021  5-6 

1904  52,690  8.0 

1905  59,340         5-8 

1906  110,804         6.4 

1907  100,816         4-1 

The  decrease  of  malaria  at  Pontepossero  and  Uniti,  the 
result  of  a  "mixed"  prophylaxis,  screening  and  quinine,  is  re- 
markable : 

Per  Cent,  of  Population 
Year.  Attacked  by  Fever. 

Before  1902  608 

1902  55-0 

1903  40.0 

1904  30.0 

1905  l6-0 

1906  9-8 


1907 


2.0 


Notwithstanding  the  favorable  experiences  recorded,  there 
are  disadvantages  in  the  employment  of  quinine  as  a  prophy- 
lactic. The  obstacles  are  much  greater  in  its  use  as  a  public 
measure  than  private. 

One  objection,  varying  considerably  with  individuals,  is  cin- 
chonism,  which  may  even  amount  to  very  unpleasant  nervous 
or  gastric  disturbance. 

To  be  efficient  as  a  preventive  of  malaria  quinine  must  be 
taken  in  sufficient  dose  during  the  entire  malarial  season.  It 
is  difficult  to  make  ignorant  people  realize  the  importance  of 
taking  treatment  during  several  months  to  prevent,  maybe, 
merely  a  chill,  and  few  governments  have  the  authority  to 
force  them  to  do  so.     No  permanent  results  are  to  be  obtained 


320  THE   STUDY   OF   MALARIA 

in  this  way  unless  all  take  the  drug  throughout  the  malarial 
season  and  all  cases  of  malaria  are  radically  cured. 

The  expense  of  public  prophylaxis  with  quinine  on  a  large 
scale  is  enormous;  in  fact,  in  some  instances  prohibitory. 
Money  spent  for  quinine  to  be  given  in  inadequate  doses  at 
irregular  intervals  is  wasted. 

The  size  of  the  dose  and  the  interval  at  which  the  prophy- 
lactic is  administered  are  of  the  utmost  importance.  Very 
varying  quantities  have  been  employed  at  different  intervals, 
but  the  established  methods  have  about  settled  down  to  those 
described  below : 

The  method  canonized  by  Koch  consists  in  giving  I  gram  of 
quinine  every  sixth  and  seventh  day,  seventh  and  eighth,  eighth 
and  ninth,  or  ninth  and  tenth  day,  according  to  the  danger  of 
infection.  This  manifestly  leaves  several  intervening  days  in 
which  there  is  no  quinine  in  the  circulation.  In  localities,  there- 
fore, in  which  estivo-autumnal  malaria  is  prevalent,  the  shorter 
interval  of  administration  should  be  preferred  on  account  of 
the  shorter  period  of  incubation  of  this  form  of  malaria. 

This  method  has  proved  very  valuable  in  many  hands. 

Ziemann48  describes  his  method  of  "universal  prophylaxis" 
as  follows : 

i.  One  gram  of  quinine  is  given  every  four  days,  three  days 
intervening.  The  drug  is  given  in  solution  with  5  drops  of 
hydrochloric  acid.  If  cinchonism  is  marked,  1  gram  of  potas- 
sium bromide  is  given. 

2.  If  1  gram  of  quinine  is  not  well  borne,  1  gram  of  euqui- 
nine  is  given. 

3.  If  this  produces  too  decided  cinchonism,  y2  gram  of 
quinine  is  given  as  above. 

4.  If  Yi  gram  of  quinine  cannot  be  taken,  ^2  gram  of  euqui- 
nine  is  administered. 

The  drug  is  given  early  in  the  morning  or  one  and  a  half  to 
two  hours  after  a  meal.  The  rule  is  to  give  a  dose  on  the  first 
of  each  month  and  thereafter  on  each  day  of  the  month 
divisible  by  four. 

By  this  method  it  is  believed  that  quinine  is  constantly  in 
the  blood  current,  and  that  this  result  is  accomplished  with  a 


PROPHYLAXIS  321 

minimum  amount  of  the  specific  necessary  for  efficient  prophy- 
laxis. 

The  method  of  Plehn,171  >4  gram  of  quinine  every  fifth 
evening,  has  already  borne  the  test  of  experience. 

The  administration  of  small  doses  of  quinine  daily  is  the 
oldest  method  of  giving  quinine  prophylactically.  From  i>4 
to  6  grains  have  been  given  daily.  It  is  probable  that  the  smaller 
amount  is  almost  entirely  a  waste,  though  in  Italy  40  centi- 
grams daily  is  the  universally  adopted  dose  and  accomplishes 
good  results.  It  is  very  doubtful,  however,  whether  such  doses 
would  prevent  relapses  in  those  already  infected. 

Nocht's  method  is  to  give  0.2  gram  of  quinine  five  times 
daily.  Though  said  to  be  efficient,  this  method  is  entirely  too 
tedious  to  become  popular. 

Doses  varying  from  0.25  to  0.50  gram  given  every  other 
day  or  every  three  days  have  been  recommended  with  favor- 
able experience. 

A  method  of  giving  quinine  for  the  prevention  of  malaria 
should  be  chosen  by  experience  in  the  region.  The  Koch 
method,  every  sixth  and  seventh  day,  has  been  satisfactory  in 
the  writer's  hands. 

The  best  form  in  which  to  employ  quinine  in  prophylaxis 
and  the  size  of  the  dose  for  children  do  not  differ  from  those 
in  the  treatment,  and  will  be  considered  in  that  section. 

The  use  of  "bitters,"  a  solution  of  quinine  in  whisky,  is  not 
to  be  recommended.  Such  a  mixture  usually  contains  too 
little  quinine  to  be  of  benefit,  and  the  use  of  whisky  in  the  hot 
season,  especially  when  followed  by  exposure  to  the  sun,  is  to 
be  condemned. 

Prophylactic  quinine  should  be  continued  for  two  or  three 
months  after  leaving  a  possible  source  of  infection,  even  if  the 
disease  has  not  been  contracted,  and,  in  the  latter  event,  for  yet 
a  longer  period. 

The  Italian  Government  has  undertaken  the  sale  of  quinine 
at  a  low  price  and  its  free  distribution. 

The  law  of  December  23,  1900,  authorized  the  Minister  of 
Finance  to  sell  publicly  the  hydrochlorate  and  the  sulphate 
of  quinine  through  the  pharmacies,  tobacco  offices,  etc.    These 
21 


322  THE    STUDY   OF   MALARIA 

preparations  are  sold  in  the  form  of  tablets  of  20  centigrams, 
and  the  price  of  a  tube  containing  ten  tablets  is,  for  the  hydro- 
chlorate,  40  centimes,  and,  for  the  sulphate,  32  centimes. 

The  law  of  November  2,  1901,  prescribes  that  laborers  are 
to  be  furnished  gratuitously  with  quinine.  The  law  considers 
malaria  as  a  disease  from  which  the  landlord  should  protect  the 
laborer,  and  the  quinine  is  furnished  by  or  charged  to  the  land- 
lord. If  the  laborer  dies  of  pernicious  malaria  and  it  is  evident 
that  death  was  due  to  a  lack  of  quinine,  the  family  of  the 
laborer  is  entitled  to  indemnity  from  the  landlord.  Govern- 
ment employes  in  malarial  localities  receive  free  quinine  from 
the  Government. 

Combinations  in  pill  form  of  quinine,  iron,  and  arsenic, 
known  as  antimalarial  pills,  are  valuable  as  tonics  and  are 
mildly  prophylactic.  They  do  not,  however,  contain  sufficient 
quinine  to  be  reliable  prophylactics,  at  least  in  this  region. 
Such  pills,  Grassi's  esanophele  pills,  were  tried  in  comparison 
with  the  sulphate  and  hydrochlorate  of  quinine  by  the  Italian 
Antimalaria  Society  and  found  to  be  less  efficient.147 

Arsenic,  so  long  vaunted  as  an  antimalarial,  has  been  thor- 
oughly tried  and  abandoned. 

Narcotine  has  some  prophylactic  value,  though,  as  evident 
from  the  experience  of  Duncan,396  it  does  not  compare  with 
quinine.  In  1896,  50  men  taking  3  grains  of  quinine  had  no 
cases  of  malaria;  50  taking  2  grains  of  narcotine  had  3  per 
cent,  of  malarial  cases,  while  those  taking  no  drug  had  6.5  per 
cent,  of  malaria.  In  1897,  50  men  taking  3  grains  of  quinine 
had  no  malaria,  50  taking  2  grains  of  narcotine  had  6  per  cent. 
of  malaria,  while  those  taking  no  drug  had  9.8  per  cent,  of 
malaria. 

Tea,  coffee,  and  lemons  have  very  slight  preventive  virtue. 

III.  MEASURES  TO  PREVENT  THE  ACCESS  OF  MOSQUITOES 
Exclusion  of  Mosquitoes. — The  prophylactic  value  of  ex- 
cluding mosquitoes  is  in  proportion  to  the  number  of  anophe- 
lines  and  the  proximity  of  infected  persons. 

A  properly  protected  house  should  have  every  door  and 
window  screened.     In  some  localities  it  is  advisable  to  cover 


Fig.  95. — The  screened  vestibule  as  employed  by  the  Italians  (Celli). 


Fig.  96. — A  model  of  house  screening. 


Fig.   97. — The  importance  of  screens  is  appreciated  by  the  shanty   boatman. 


|a|HBB|HiHH^HHHHHI 

■ '  ~,ftHgwto**SSSB&* * '' 

SSSKr 

Fig.  98. — Im 


Fig.     99.— Prop 


mosquito 


netting. 


netting. 


PROPHYLAXIS  323 

even  the  chimneys  with  wire  netting.  Doors  should  be  pro- 
vided with  springs  to  necessitate  closure.  Where  mosquitoes 
are  plentiful,  and  a  door  is  much  used,  a  double  door,  with  an 
intervening  vestibule,  after  the  manner  of  the  Italians  (Fig. 
95),  is  to  be  preferred.  A  screened  porch  permits  of  sitting 
in  the  air  in  the  evening  when  it  would  be  dangerous  to  do  so 
otherwise. 

The  selection  of  the  gauze  for  screens  is  of  the  highest 
importance.  The  mesh  of  the  wire  netting  often  used.  No.  12, 
is  too  large,  permitting  small  mosquitoes  to  pass  (Figs.  98 
and  99).  None  should  be  used  with  fewer  meshes  than  18 
to  the  inch.  In  the  absence  of  wire  gauze,  cotton  mosquito 
netting  may  be  employed,  but,  being  frail,  soon  becomes  torn 
and  useless. 

Persons  whose  ocupations  keep  them  out  at  night  in  highly 
malarial  places,  as  watchmen  and  others,  should  be  protected 
with  veils  and  with  leather  gloves  having  gauntlets. 

The  mosquito  bar  is  indispensable  in  malarial  countries.  Be- 
sides being  very  effective  when  properly  adjusted,  it  is  the 
most  inexpensive  of  all  prophylactic  methods. 

Stephens  and  Christophers113  relied  personally  almost  en- 
tirely upon  the  protection  afforded  by  the  mosquito  bar.  They 
say:  "The  net  should  be  square  (not  a  bell  net)  ;  should  not 
have  a  single,  even  minute,  hole ;  should  hang  outside  the  poles, 
if  these  are  used;  should  be  tucked  under  the  mattress,  and 
should  not  trail  on  the  ground.  A  piece  of  closely  woven  mate- 
rial, fastened  on  all  round  at  the  level  of  the  body,  is  a  neces- 
sary addition  in  order  to  protect  the  limbs  during  sleep  from 
bites  through  the  net.  When  not  in  use  the  ends  of  the  net 
should  be  twisted  up  somewhat  and  then  thrown  over  the  top. 
We  always  arranged  our  nets  ourselves,  never  trusting  to  ser- 
vants, and,  further,  to  be  doubly  certain,  we  always  carefully 
searched  the  interior  with  a  candle  before  going  to  sleep.  To 
these  minute  precautions  solely  we  attribute  our  absolute  free- 
dom from  malaria.  Employed  without  care  and  attention  a 
mosquito  net  is  of  little  protection  in  such  malarious  places  as 
most  up-country  African  stations." 

The  Public  Health  and  Marine  Hospital  Service  issues  the 


324 


THE   STUDY  OF   MALARIA 


following  instructions  in  regard  to  screening  against  mos- 
quitoes :397 

i.  The  netting  used  should  have  meshes  fine  enough  to 
prevent  the  passage  of  mosquitoes  (at  least  18-20  to  the  inch). 

2.  It  is  important  to  screen  the  windows  and  doors  of  the 
house.  It  is  doubly  important  to  screen  the  beds  of  fever 
patients. 

3.  Mosquitoes  can  bite  through  the  mosquito  nets  when  any 
part  of  the  body  is  in  contact  with  the  netting. 

4.  Frequent  examinations  should  be  made  to  see  that  there 
are  no  torn  places  in  the  netting  or  that  no  mosquitoes  have 
found  a  lodging  inside. 

5.  The  netting  should  be  well  tucked  in  to  keep  mosquitoes 
from  entering. 


Fig.  100. — British  experimental  hut  near  Ostia  (Manson). 

6.  If  mosquitoes  are  found  within  the  netting  they  should 
be  killed  inside,  and  not  merely  driven  or  shaken  out. 

The  results  obtained  from  mechanical  prophylaxis  have  been 
very  satisfactory.  The  celebrated  experiment  of  Sambon  and 
Low398  is  striking.  Under  the  auspices  of  the  English  Colonial 
Office  and  the  London  School  of  Tropic  Medicine  these  scien- 
tists spent  the  entire  malarial  season  of  1900  near  Ostia,  in  one 
of  the  most  malarial  parts  of  the  Roman  Campagna.  The  hut 
in  which  they  lived  was  constructed  in  London  for  the  purpose, 
and  was  thoroughly  screened.  They  drank  the  same  water  and 
worked  in  the  marsh  with  the  natives.  They  took  no  quinine, 
and,  in  fact,  observed  no  prophylactic  precautions  excepting  to 


PROPHYLAXIS  325 

remain  in  the  house  from  sunset  to  sunrise.  Though  malaria 
and  anopheline  mosquitoes  were  abundant  about  them,  they  re- 
mained the  entire  season  without  becoming  infected  with 
malaria. 

The  following  figures  show  the  results  obtained  by  the  Italian 
Society  for  the  Study  of  Malaria.147  Of  802  persons  incom- 
pletely protected  10.9  per  cent,  had  primary  infections;  of 
5,165  protected  more  or  less  completely  there  were  3.3  per 
cent,  of  primary  infections ;  while  among  4,363  persons  com- 
pletely protected  there  were  only  1.9  per  cent,  of  primary  in- 
fections. Among  unprotected  persons  in  the  same  regions  the 
proportion  varied  between  40  to  60  per  cent. 

The  following  experiment  was  conducted  by  the  Japanese 
military  authorities  upon  the  Island  of  Formosa.  A  company 
of  115  men  was  completely  protected  against  mosquitoes,  with 
the  result  that  not  a  single  case  of  malaria  occurred  in  the 
company.  The  rest  of  the  battalion,  numbering  646  men,  was 
unprotected,  and  282  cases  of  malaria,  with  a  mortality  of  1.12 
per  cent.,  occurred  among  them.86 

At  the  custom-house  barracks  at  Porto- Vecchio  there  were 
in  1901  among  23  persons  14  cases  of  malaria.  In  1902,  after 
the  installation  of  metal  screens,  there  was  not  a  single  case  in 
the  same  force.86 

In  one  of  the  most  insalubrious  localities  in  Corsica  there 
were  in  1904  among  153  individuals  80  cases  of  malaria. 
Screens  were  put  up  in  1905,  and  during  the  year  there  were 
only  7  primary  cases. 

Schoo's90  results  with  screening  in  Holland  were  favorable. 
Among  47  inhabitants  there  were  18  cases  of  malaria  in  1901. 
Screens  were  installed  March,  1902,  and  not  a  single  fresh 
infection  occurred.  Of  58  unprotected  persons  there  were  8 
cases  of  malaria  in  1901,  and  in  1902  there  were  19  cases. 

As  with  every  other  method  for  the  prevention  of  malaria, 
screens  have  certain  shortcomings.  It  is  evident  that  if  malaria 
is  to  be  eradicated  by  these  means  from  a  locality  every  house 
should  be  screened,  otherwise  only  those  in  the  protected  houses 
would  be  exempt,  and  only  so  long  as  they  remain  in  such 
houses.     It  is  out  of  the  question  in  many  malarial  places  to 


326  THE    STUDY    OF    MALARIA 

consider  the  screening  of  all  the  houses,  both  on  account  of 
the  expense  and  because  of  the  poor  construction  of  many  of 
them,  permitting  mosquitoes  to  enter  through  crevices  and 
other  openings.  The  fact  that  screens  offer  a  slight  hindrance 
to  the  free  circulation  of  air  in  hot  countries  is  of  little  moment 
in  the  face  of  the  benefits  derived  from  their  use,  and  they 
must  be  considered  as  one  of  the  most  effective  means  of 
private  prophylaxis.    . 

Of  local  applications  to  drive  away  mosquitoes  many  sub- 
stances have  been  tried,  particularly  the  essential  oils,  of  which 
the  oils  of  citronella,  eucalyptus,  and  lavender  are  probably  the 
most  efficacious.  Petroleum,  infusion  of  quassia,  naphthaline, 
powdered  sulphur,  camphor,  garlic,  the  oils  of  cloves,  tar, 
pennyroyal,  chrysanthemum,  and  anise  have  been  employed 
with  varying  degrees  of  success. 

The  following  preparations  are  highly  recommended : 

Cedar  oil    1  ounce ; 

Oil  of  citronella  2  ounces ; 

Spirits  of  camphor  2  ounces. — M. 

Sig. :  Apply  a  few  drops  to  a  cloth  and  hang  upon  the  bed.12* 

A"'} »'.««! 

Oil  of  lavender  1  dram. — M. 

Sig. :  Apply  to  the  skin.122 

Quinine-glycerine 1 :  1000 

Sig. :  Apply  to  the  skin." 


Alcohol 


Ether,      \ 

01.  eucalyptus     j 


aa    5.0 


Aq.  colomensis,  ,  aa  Ia0 


Tr.  pyrethrum    15.0.— M. 

Sig. :  Dilute  with  four  or  five  parts  of  water  and  apply  to 
the    skin.48 

For  the  local  relief  of  mosquito  bites,  touching  with  water 
of  ammonia  or  with  glycerin  are  efficient. 

In  India  the  punka  is  employed  to  keep  the  air  in  motion,  and 
for  this  reason  is  found  to  be  of  service  in  driving  away  mos- 
quitoes. The  electric  fan  has  this  effect  also,  but  for  obvious 
reasons  should  not  be  employed  for  this  purpose  during  sleep. 

The  value  of  smoke  against  mosquitoes  is  well  known, 
though  it  is  not  always  entirely  effective.  The  writer  recalls  an 
occason  while  on  an  island  off  the  Gulf  coast  of  Florida  where 


PROPHYLAXIS  327 

smoke  was  of  no  avail  against  the  terrific  onslaught  of  blood- 
thirsty mosquitoes,  and  it  became  necessary  to  bury  himself  up 
to  the  neck  in  the  sand  and  to  cover  the  head  with  a  coat. 

Isolation  of  the  malarial  patient  is  as  truly  indicated  as  in 
yellow  fever,  both  diseases  being  conveyed  in  the  same  manner. 
Mosquitoes  must  become  infected  before  they  can  infect  man ; 
breaking  the  vicious  circle  at  this  point  would  extirpate  mala- 
ria. Isolation  is  demanded  not  only  for  the  good  of  the  com- 
munity, but  to  prevent  reinfection  of  the  patient,  who  should 
be  confined  under  a  well-adjusted  bar  until  a  radical  cure  is 
effected.  It  is  not  to  be  expected,  however,  that  as  much  can 
be  accomplished  from  the  isolation  of  malaria  as  from  isola- 
tion of  yellow  fever.  Many  cases  of  malaria  entirely  escape 
medical  treatment,  and  a  malarial  subject  may  be  a  source  of 
infection  for  a  year  or  more,  while  yellow  fever  is  infectious 
for  only  a  few  days. 

Since  it  has  become  evident  that  so  great  a  proportion  of 
the  inhabitants,  especially  the  children  of  tropic  countries, 
harbor  malarial  parasites  in  the  blood,  segregation  of  the 
whites  from  the  natives  has  been  proposed  and  in  some  in- 
stances practised  with  success.  While  the  question  is  of  some 
import  in  this  country,  the  negro  quarters  in  most  of  our 
towns  are  fairly  well  defined  from  those  of  the  white.  Upon 
the  premises  the  householder  should  see  that  his  servants' 
quarters  are  as  thoroughly  screened  as  his  own.  In  the  choice 
of  camp  sites  native  houses  should  be  avoided  beyond  the 
limit  of  flight  of  mosquitoes,  if  possible. 

Great  good  is  being-  accomplished  in  the  prophylaxis  of 
tuberculosis  by  education,  keeping  the  main  facts  in  the  etiology 
and  prevention  constantly  before  the  eyes  of  the  people.  So 
much  cannot  be  expected  for  malaria  on  account  of  the  igno- 
rance and  carelessness  of  the  class  and  race  of  people  most 
scourged,  but  undoubtedly  some  good  may  accrue  from  this 
method.  The  Europeans,  at  home  and  in  their  colonies,  have 
obtained  some  results  in  the  prophylaxis  of  malaria  by  teach- 
ing the  people  the  elements  of  the  cause  and  prevention  of 
the  disease. 

Lectures,  illustrated  by  stereopticon  views,  are  held  publicly. 


328  THE    STUDY   OF    MALARIA 

Publications  in  simple  language,  in  the  form  of  circulars  and 
tracts,  and  even  appropriately  illustrated  postcards  are  scat- 
tered broadcast.  The  Italian  Society  for  the  Study  of  Malaria 
has  distributed  about  two  millions  of  these  circulars.  The 
principles  of  prophylaxis  are  instilled  into  the  minds  of  the 
school  children,  and  made  attractive  and  impressed  by  means 
of  illustrated  charts.  The  lay  press  has  been  used  to  advan- 
tage. With  such  means  the  formation  of  an  antimalarial 
league  can  do  much  for  a  community.  A  little  can  be  accom- 
plished by  education,  and  this  little  should  not  be  neglected. 

Schools  and  departments  of  tropic  medicine  have  done  a 
great  deal  to  disseminate  a  knowledge  of  this  very  important 
subject,  and  even  more  stress  should  be  laid  upon  this  impor- 
tant branch  of  medical  science. 

To  be  thorough,  malarial  prophylaxis  should  be  handled 
by  the  Government.  Destruction  of  the  breeding  places  of 
the  mosquitoes,  which  is  by  far  the  most  radical  method,  is, 
in  many  instances,  too  expensive  to  be  done  by  individuals. 
The  formation  of  drainage  districts,  the  expenses  of  which  are 
paid  by  those  benefited,  is  an  effective  plan,  and  so  enhances 
the  value  of  real  estate,  from  both  agricultural  and  sanitary 
standpoints,  that  there  should  be  no  opposition.  The  writer 
is  convinced  that  these  districts,  which  are  being  formed  in 
various  parts  of  the  South,  are  decreasing  the  malaria  in  a 
decided  degree.  It  is  highly  probable  that  malaria  will  be 
exterminated  as  a  natural  consequence  of  the  drainage  of  the 
soil  before  the  Government  or  the  people  are  educated  to 
the  point  of  taking  prophylactic  steps.  Governments  will 
spend  millions  of  money  in  the  eradication  of  malaria  from 
foreign  laborers  in  order  to  further  gigantic  commercial  enter- 
prises, but  make  no  prophylactic  efforts  against  the  malaria 
undermining  the  vitality  and  destroying  the  lives  of  citizens. 
Individuals  who  should  know  better  permit  anopheles  mosqui- 
toes to  breed  at  their  doors  and  to  have  access  to  their  houses, 
and  allow  their  malaria  to  go  untreated. 

The  International  Congress  of  Hygiene  at  its  Brussels 
meeting,  September,  1903,  recommended  to  all  Governments 
the  adoption  of  the  following  measures  :144 


PROPHYLAXIS  329 

1.  All  officers,  administrators,  or  employes  before  entering 
the  service  of  the  country  should  give  proof  of  a  knowledge 
of  the  epidemiology  of  malaria  and  its  practical  application. 

2.  In  all  countries,  places  of  instruction,  depending  upon 
either  the  Government,  missions,  or  otherwise,  are  urged  to 
include  in  the  curricula  a  teaching  of  the  knowledge  of  the 
propagation  of  malaria,  and  the  practical  applications  which 
proceed  therefrom. 

3.  Officers,  administrators,  or  employes  ignorant  of  these 
facts  or  persistently  refusing  to  apply  them  are  to  be  consid- 
ered unfit  for  service  in  malarial  countries. 

The  almost  miraculous  results  in  the  prophylaxis  of  malaria 
which  may  be  obtained  by  a  willing  and  wealthy  Government 
are  exemplified  in  the  sanitation  of  the  canal  zone  previously 
referred  to.  The  means  of  accomplishing  this  end  are  thus 
briefly  described  by  Busck:399 

"In  the  beginning  the  land  is  cleared  by  the  removal  of  all 
brush,  undergrowth,  and  grass;  only  shade  and  fruit  trees  are 
left,  and  these  are  thinned  out  to  admit  sunlight  and  free 
ventilation.  Where  possible,  swamps  and  lowlands  are  filled 
in,  the  immense  excavations  at  the  Culebra  cut  furnishing 
abundant  material.  Then  the  whole  area  is  drained  to  carry 
off  the  surface  water  or  any  constant  flow  from  springs  or 
seepage  from  the  hills.  This  drainage  is  extended  to  all  new 
work  in  the  canal  cut  and  to  railroad  work  or  dumps  near 
settlements.  The  drainage  is  accomplished  by  subsoil  tile- 
drains,  open  ditches,  and  open  concrete  or  stone  and  cement 
ditches.  Drain  tiling  or  cement  ditches  are  made  where  pos- 
sible, as  they  require  very  little  care  afterward,  while  the  open 
dirt  ditches  must  be  constantly  cleaned  and  regraded  to  pre- 
vent 'pocketing'  and  the  consequent  formation  of  breeding 
pools  for  mosquitoes.  In  open  dirt  ditches  the  algse  will  form 
in  two  or  three  days  after  cleaning,  and  to  prevent  this  drip 
cans  are  placed  at  the  head  of  those  ditches  with  a  solution 
of  sulphate  of  copper,  5  pounds  to  a  barrel  of  50  gallons  of 
water.  This  is  also  used  in  all  running  streams  after  the 
removal  of  algse. 

"Open  ditches  in  which  the  water  flows  sluggishly  have  oil 


330  THE   STUDY  OF  MALARIA 

drip-cans  at  their  heads.  The  oil  cans  are  raised  three  feet 
above  the  water  to  give  a  wide  spread  to  each  drop,  and  are 
arranged  to  drop  about  20  drops  to  the  minute.  The  oil  used 
is  a  rather  heavy  dark  grade,  which  costs  the  department  $4.34 
a  barrel.  About  3,200  barrels  of  oil  were  used  within  the  last 
year. 

"All  streams  are  kept  free  from  algae  and  are  kept  within 
restricted  banks  as  far  as  possible ;  this  is  done  by  blowing  out 
the  rapids  or  falls  to  produce  a  uniform  flow,  and  the  edges 
are  filled  in  by  hand. 

"All  swamps,  pools,  or  even  temporary  collections  of  water 
are  oiled  at  least  weekly,  and  in  the  rainy  season  oftener; 
this  applies  to  the  smallest  collection  of  water,  even  animal 
tracks,  ruts  from  wagon  wheels,  and  crab  holes.  It  entails  a 
great  amount  of  work,  which  is  done  by  colored  labor  under 
continual  supervision. 

"All  receptacles  holding  water  must  be  screened  or  oiled. 
Water  barrels  are  screened  by  covering  with  a  board  with  a 
small,  screened  opening  in  the  center  for  the  inflow.  Below 
this  board  are  two  screened  holes  for  the  overflow,  and  the 
water  is  drawn  from  a  faucet  at  the  bottom.  Buckets  and 
pails  in  daily  use  in  a  household  are  not  permitted  to  stand 
filled  more  than  twenty-four  hours.  All  tin  cans,  bottles,  etc., 
must  be  buried.  No  gutters  are  allowed  on  houses.  There  is 
a  daily  inspection  of  all  water  receptacles,  and  weekly  the 
inspector  at  the  head  of  the  station  must  make  a  personal 
inspection  and  report  any  receptacle  found  containing  mosquito 
larvae.  The  second  offense,  after  a  warning,  means  the  arrest 
and  fine  of  the  householder. 

"All  old  machinery,  which  is  found  in  great  quantity  all  over 
the  zone  canal,  left  from  the  French  occupation,  is  drained 
by  punching  holes  in  any  part  that  will  hold  water  or,  where 
this  is  not  possible,  such  places  are  filled  with  dirt. 

"Even  patent  car  couplings  on  the  trains  in  use  must  be 
inspected  and  oiled,  as  they  are  often  found  to  contain  mos- 
quito larvae. 

"When  any  house  or  camp  is  found  to  contain  any  number 
of  mosquitoes  it  is  fumigated  with  sulphur  by  the  dry  method. 


PROPHYLAXIS  331 

All  cracks  or  openings  are  pasted  over  with  paper;  enough 
pots,  each  containing  5  pounds  of  sulphur,  are  placed  at  inter- 
vals on  the  floors  to  make  about  1  pot  for  each  1,000  cubic 
feet  of  space.  After  fumigation  the  house  is  left  closed  from 
three  to  four  hours. 

"All  barracks,  whether  for  black  or  white  laborers,  bachelor 
quarters,  married  quarters,  offices,  churches,  lodge-rooms,  and 
other  rooms  used  for  sleeping,  living,  or  eating  quarters  are 
screened.  The  Sanitary  Department  is  responsible  for  all  re- 
pairs of  this  screening,  and  employs  a  large  force  of  carpenters 
for  this  purpose. 

"The  physicians  in  each  district  make  a  weekly  report  on 
the  number  of  cases  of  malaria  in  the  different  camps;  these 
reports  are  tabulated  in  the  central  office  of  the  Sanitary  De- 
partment and  compared  with  the  previous  records,  and  if  an 
increase  of  even  a  fraction  of  1  per  cent,  is  shown  for  any 
locality  the  local  inspector  is  telephoned  and  ordered  to  locate 
the  point  of  infection  and  eradicate  the  breeding  places.  Long- 
continued  statistics  show  how  nicely  this  system  works.  If 
any  more  serious  increase  occurs  a  special  mosquito  inspector 
is  sent  out  from  the  central  office  to  locate  the  trouble  and 
report  on  the  best  measures  to  be  taken. 

"The  difficulties  of  this  work  are  numerous.  The  constant 
increase  of  population  requires  new  sites  for  camps  to  be 
made  in  the  unimproved,  brush-covered  country;  the  ever- 
changing  conditions  due  to  the  canal  work  are  a  continued 
source  of  trouble ;  the  progress  of  each  steam-shovel  or  of 
each  of  the  extensive  dumps  produces  new  problems  to  be 
solved  in  the  way  of  drainage,  and,  above  all,  the  recurring 
deluges  of  the  rainy  season  cause  rising  creeks  and  rivers  and 
overflow  of  lowlands  so  irregular  as  to  be  impossible  to  fore- 
see. 

"The  Sanitary  Department  has,  aside  from  its  office  force, 
about  thirty  sanitary  inspectors  and  employs  between  1,200 
and  1,300  laborers.  The  total  cost  of  the  Sanitary  Inspector's 
Department  is  between  three  and  four  hundred  thousand  dol- 
lars." 

It  should  be  the  duty  of  the  authorities  of  every  malarial 


332  THE    STUDY   OF   MALARIA 

country  to  remove  the  duty  from  quinine  and  to  maintain  a 
high  standard  of  purity  and  a  low  price. 

In  military  practice  permanent  quarters  should  be  properly 
screened,  and  all  breeding  pools  within  the  radius  of  danger 
should  be  destroyed.  .  Temporary  quarters  should  be  chosen 
with  reference  to  the  breeding  of  mosquitoes,  and  the  force 
should,  if  necessary,  be  subjected  to  Koch's  quinine  pro- 
phylaxis. Ships  should  not  anchor  too  near  the  shore  of 
malarial  localities. 

Private  prophylaxis  consists  of  measures  having  reference 
to  the  person  and  to  the  premises.  Personal  prophylaxis  is 
synonymous  with  proper  hygiene.  Suitable  food,  water,  and 
clothing  are  essential.  Regular  hours  must  be  kept,  and  con- 
stipation, chilling  of  the  body,  and  excesses  of  all  kinds  must 
be  avoided.  Prophylactic  quinine  is  not  constantly  necessary 
for  residents  if  the  premises  are  in  proper  condition,  but  is 
suitable  for  strangers  and  under  conditions  where  mosquitoes 
cannot  be  excluded.  Persons  sleeping  upstairs  are  less  liable 
to  infection  than  those  upon  the  first  floor. 

Pools  are  to  be  filled,  drained,  or  oiled,  and  vessels  emptied. 
It  has  been  suggested  that  a  tub  of  water  be  kept  on  the  place 
to  tempt  mosquitoes  to  breed,  and  that  this  be  emptied  every 
few  days.  Stock  ponds  should  be  drained,  oiled,  or  stocked 
with  fish.  The  houses  should  be  thoroughly  screened,  and 
where  these  are  not  effective,  or  if  infection  occurs,  bars  must 
be  employed. 

PROPHYLAXIS  OF  HEMOGLOBINURIC  FEVER 
A.  Plehn  has  shown  that  hemoglobinuric  fever  is  prevent- 
able to  a  greater  degree  even  than  malaria.  In  1897-99  among 
the  officers  of  Cameroon  who  used  no  prophylactic  there  oc- 
curred in  578  months  of  residence  287  cases  of  malaria  and 
31  of  blackwater  fever,  or  1  malaria  case  for  every  two 
months  and  1  of  blackwater  fever  for  each  18.5  months.  Ten 
per  cent,  of  the  blackwater  cases  terminated  fatally.  During 
the  same  period  among  those  who  used  prophylaxis  there  were 
in  446  months  of  residence  90  cases  of  malaria  and  6  of  hemo- 
globinuric fever,  or  1  case  of  malaria  for  each  five  months 


PROPHYLAXIS  333 

of  residence  and  I  of  hemoglobinuria  fever  for  each  seventy- 
four  months,  none  of  which  were  fatal.  Thus,  while  malaria 
was  reduced  by  half,  the  morbidity  of  blackwater  fever  was 
lowered  to  one-fourth.  The  lowered  mortality  of  these  cases 
is  even  still  more  remarkable ;  similar  results  were  observed  by 
Moffatt.263  Even  Koch90  believes  that  through  appropriate 
quinine  prophylaxis  not  only  malaria,  but  blackwater  fever  in 
an  overwhelming  majority  of  instances  can  be  exterminated. 

The  prophylaxis  of  hemoglobinuric  fever  consists  of  the 
prophylaxis  and  proper  treatment  of  malaria.  There  are  two 
chief  methods  in  vogue  for  the  use  of  quinine  as  a  preventive 
of  hemoglobinuric  fever:  Plehn's  method,  ^2  gram  every 
fifth  evening,  and  Koch's,  1  gram  on  two  successive  days. 

The  results  of  A.  Plehn,  recorded  above,  were  obtained 
with  ]/2  -gram  prophylaxis,  but  Ruge158  maintains  that  better 
consequences  follow  Koch's  method,  and  gives  the  following 
figures:  According  to  the  1903  statistics  of  Cameroon,  there 
were  among  those  who  used  quinine  regularly  12  cases  of 
blackwater  fever,  of  which  8  employed  the  Plehn  method,  3 
first  Plehn's,  then  Koch's,  and  only  1  Koch's  method  regularly. 
Of  35  cases  among  irregular  users  17  employed  the  J^-gram 
method  and  only  3  the  i-gram  method.  From  these  figures  it 
is  evident  that  Koch's  method  is  preferable  even  when  not 
systematically  employed. 

It  is  necessary  to  persist  in  prophylaxis  not  only  while  in 
the  blackwater  fever  district,  but  for  several  months  there- 
after. As  a  majority  of  the  first  cases  occur  from  the  second 
to  the  fourth  year  of  residence,  it  is  evident  that  greater  care 
should  be  exerted  during  this  period. 


CHAPTER  IX 

TREATMENT 

The  use  of  cinchona,  whose  discovery,  made  by  an.  uncivil- 
ized people,  was  one  of  the  most  valuable  in  the  history  of 
medicine,  was  at  first  bitterly  opposed  by  the  medical  profession. 
Sydenham,  Morton,  and  Torti  had  in  a  measure  removed  the 
prejudice  against  the  drug  when  the  work  of  Johnson,16  the 
most  pernicious  medical  book  of  the  nineteenth  century,  ap- 
peared and  largely  undid  their  teaching.  After  much  suffering 
and  waste  of  life  quinine  has  come  to  be  regarded  as  almost 
specific  for  malaria. 

The  word  "almost"  is  used  intentionally,  for,  while  quinine 
is  more  nearly  specific  than  any  other  known  drug,  it  has  limita- 
tions. While  the  clinical  manifestations  of  malaria  ■  usually 
subside  readily  after  quinine,  a  radical  cure  is  sometimes  diffi- 
cult. A  few  grains  a  day  will  relieve  many  cases,  though  a 
dram  a  day  will  not  save  some  patients.  A  few  of  the  sequelae 
of  malaria  are  but  little,  if  at  all,  influenced  by  quinine. 

Among  the  alkaloids  of  cinchona  bark  quinine  is  the  one 
now  generally  used.  The  following  table  shows  the  alkaloidal 
strength  of  the  various  salts  of  quinine,  as  well  as  their  solu- 
bility : 


Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 

Euqu 


c  ,.                                                                        Per  Cent,  of  Solubility  in  Parts 

balt-                                                                          Alkaloid.  of  Water. 

ne,  anhydrous    ioo  i,75o 

ne  acetate   84  Slightly 

ne  bimuriate  (or  acid  hydrochloride)...   71  Less  than  its  weight 

ne  bisulphate 59  8.5 

ne  citrate    67  820 

ne  hydrobromide  76  40 

ne  lactate  78  10 

ne  hydrochloride   81  18 

ne  salicylate 68  J7 

ne  sulphate    74  720 

ne  tannate,  about 30  800 

ne  valerianate 76  53 

nine   81  12,500 

334 


TREATMENT 


335 


The  duration  of  malaria  under  quinine  treatment  has  been 
considered.  Acute  infections  are  usually  more  amenable  than 
chronic,  though  it  has  been  repeatedly  observed  that  it  requires 
less  quinine  to  control  the  paroxysms  after  the  lapse  of  four 
or  five  than  when  the  specific  is  given  early  in  the  attack. 

Absorption  and  Elimination  of  Quinine. — Most  of  the 
salts  are  readily  absorbed  from  the  stomach.  It  has  been 
shown,  however,  that  the  tannate  is  more  largely  absorbed 
from  the  small  intestine. 


5  3  3 

!  1 a 

III 

tffl'tna. 

380 

a£o 

310 

310 
300 
T.%0 
liO 

a.4o 

W<> 
wo 
/«o 

lt.0 

m 
if 

to 
60 
40 

2* 

1  tn.OMn.1 

ffUUW' 

Fig.  ioi. — Average  results  of  the  quantitative  determination  of  the  excretion  of  quinine 
in  the  urine  (after  Mariani). 

The  rapidity  of  absorption  varies  with  the  different  salts, 
and  is  estimated  by  the  length  of  time  required  to  appear  in 
the  urine.  The  time  from  the  administration  of  the  drug  until 
it  begins  to  appear  in  the  urine  is  represented  as  follows : 


Hydrochloride  15  minutes 

Bisulphate     30  minutes 

Sulphate    45  minutes 

Acetate 30  minutes 

Citrate    30  minutes 

Tannate   3  hours 


336  THE    STUDY    OF    MALARIA 

The  method  of  administration  of  quinine  also  influences  the 
rapidity  with  which  it  is  absorbed. 

Given  by  the  mouth,  a  highly  soluble  salt  will  begin  to 
appear  in  the  urine  within  fifteen  to  thirty  minutes,  and  is 
eliminated  in  the  greatest  quantity  within  three  to  twelve  hours. 

Mariani84  thus  tabulates  the  results  of  his  experiments : 

Contents  of  each  individual  portion  of  urine.     Date  of  successive 
emissions  of  urine. 


Form  and  mode  of  administration.      3        3  3  .  M  w  ES3^!-3^^ 

a        a  a  u  u  u  3       3^     3      3„      3       3 

•3-3  "3  3  3  3  oo^22S22 

S        S  a  o  o  o  a      -a'3)    A     A~%     a      J3 

M-,  O  10  N  Tt'3       *o       00 '3  o  N 

Muriate  of  quinine,  25  per 

cent,   solution,   subcuta- 

neously  1       3      5     12    24     18    25      7       1 

Muriate  of  quinine,  1  per 

cent,  solution,  in  spring 

water 1      4      S     12     24    20     16      5      2       1 

Muriate  of  quinine,  1  per 

cent,   solution  with  200 

cc.  carbonated  water...     1      4      4      8     15     19    30     12      2      1 
Muriate  of  quinine,  1  per 

cent,   solution  with   150 

cc.     spring     water,     by 

rectum _ 1      4      9     16     16     14      9      2 

Muriate  of  quinine,  1  per 

cent,   solution  with   150 

cc.  carbonated  water,  in 

an  hour  another  150  cc, 

by  rectum    ..... .. .     1       5       5     10     19    28     15      5      4 

Bisulphate  of  quinine,  with 

sugar      of      milk      and 

sodium  bicarbonate,   by 

mouth  1       2      6     14    26     19     16      6      2 

Carbonate  of  quinine,  by 

mouth,     with     200     cc. 

carbonated  water 1      4      4     10     12    22     15     12     10      3 

Sulphate    of    quinine,    by 

mouth 5      6     13    25     18     15      8      4      1 

Acetate     of     quinine,     by 

mouth   2      5      6     13     27     16     12      8      3 

Citrate     of     quinine,     by 

mouth 1       4      7     15     29     14     10      7      4      1 

Chinoidin  with  gum  ara- 
ble, by  mouth 8    10    38    22      8      5      2 

Tannate  of  quinine 1       2      9    28     14      4      2      2 

Pulverized      bark,       sus- 
pended in  water 2      3      4      9      6      3       x 

With  reference  to  the  influence  of  food  in  the  stomach  upon 

the  rate  of  absorption,  Kleine's400  experiments  tend  to  show 

that  quinine  is  much  more  slowly  absorbed  from  a  full  than 

from  a  fasting  stomach.     The  minute  researches  of  Mariani 

prove,  however,  that,  while  the  presence  of  food  in  the  stomach 


TREATMENT 


337 


retards  the  absorption  of  quinine  during  the  first  six  hours 
after  administration,  the  quantity  absorbed  during  the  entire 
twenty-four  hours  after  administration  is  greater  from  a  full 
than  from  an  empty  stomach,  and  is  absorbed  in  greater  quan- 
tities even  during  the  second  and  third  days.  He  explains 
this  by  the  theory  that  the  liver  is  able  to  dispose  of  only  a 
small  quantity  of  the  alkaloid  when  it  arrives  together  with 
the  products  of  digestion. 

Giemsa  and  Schaumann300  investigated  the  subject,  with  the 
following  results :  After  the  administration  of  i  gram  of 
quinine  upon  an  empty  stomach  the  excretion  by  the  urine 


Fig.  102. — Excretion  of  large  doses  of  quinine  (after  Kleine). 

Quinine  muriate,  i.o,  by  mouth,  empty  stomach. 

Quinine  muriate,  2.0,  in  enema. 

Quinine  muriate,  2.0,  by  mouth,  three  hours  after  eating. 


— .  — .  — .  —  Quinine  muriate,  0.5,  subcutaneously. 

during  the  first  twenty-four  hours  reached  23.6  per  cent. ;  the 
same  amount  administered  during  a  meal  was  followed  by 
the  excretion  of  22.7  per  cent,  during  the  first  twenty-four 
hours.  The  quantity  excreted  during  three  days  after  the 
administration  of  1  gram  upon  an  empty  stomach  was  38.93 
per  cent. ;  during  the  same  period  following  1  gram  at  meal 
time  the  quantity  excreted  was  39.8  per  cent. 

These  investigators  found  that  the  elimination  of  quinine 
by  the  urine  is  about  one-sixth  greater  when  administered  in 
five  daily  doses  than  in  a  single  dose.  The  results  of  their 
experiments  are  thus  tabulated : 


33& 


THE    STUDY    OF    MALARIA 


Table  I 

One  gram  daily  of  quinine  hydrochloride  in  water,  at  a  single  dose,  by 
mouth. 

No.  Patient. 


First  day   18.5  26.0 

Second  day 20.8  28.5 

Third  day    19.0  29.5 

Fourth  day    19.8  29.8 

Fifth  day  19.2  29.6 

Sixth  day 20.4  27.4 

Seventh  day 29.9 

Eighth  day 28.4 

Ninth  day    28.6 

Tenth  day 29.6 

Average 19.6  28.7 


2.  3.  4.  5.  6. 

Total  quantity  of  urine  excreted  in  per  cent. 


31-5 
32.4 
33-2 
42.2 
24.2 
29.4 
30.6 


29-3 


8.5 
12,5 

1 0.0 
18.3 

18. 1 
12.2 
12.8 

154 

15-0 


24.4 
29.2 
27.4 
27.2 
24.2 
26.2 


24.8 
25-5 
25-9 
14.4 
18.4 
14.2 
24.2 
24.9 


26.5 
28.5 
28.0 


13.6        26.4        21.5        27.6 


Total  average,  23.8  per  cent. 
Remarks. — In  patient  No.  4  the  feces  were  examined,  in  which  only  a 
trace  of  quinine  could  be  detected  with  the  thalleo-quinine  reaction. 


Table 

II 

One  gram  daily  of 

quinine 

hydrochloride 

in  wafers 

,  .2  gram  every 

two 

hours. 

No. 

Patient. 

1. 

2. 

3- 

4- 

5- 

6. 

7- 

8. 

Total  quantity  of  urine  excreted  in  per  cent 

First  day  .... 

.   16.8 

14-3 

14.4 

18.8 

149 

16.6 

18.9 

l6.0 

Second  dav  . . 

.  28.9 

31.8 

26.9 

32.0 

26.I 

30.1 

34-5 

Third  day   . . . 

.  29.2 

29.7 

26.8 

32.1 

24.I 

30.4 

354 

Fourth  day   .  . 

•  29.4 

33-8 

29.1 

29.2 

24.I 

30.3 

3S-0 

Fifth  day  .... 

•  30.1 

33-9 

29.2 

28.0 

28.2 

29.2 

32.8 

29.9 

Sixth  day   . . . 

•  27.3 

32.9 

294 

27.9 

31-4 

30.2 

Seventh  day  . 

.  27.1 

29.0 

29.4 

29.2 

30.4 

Eighth  day   . . 

29.8 

29.9 

28.1 

29.I 

Ninth  day  . . . 

33-2 

294 

Tenth  day  . . . 

33-0 

28.6 

Average  . 

.  27.0 

30.1 

25.2 

28.6 

24.2 

28.1 

31-3 

27.6 

Total  average,  27.8  per  cent. 
Remarks. — In  patient  No.  8  the  urine  of  second,  third,  and  fourth  days 
were  thrown  out  by  mistake.     In  patient  No.  3  the  feces  were  examined: 
only  traces  of  quinine  could  be  detected  by  the  thalleo-quinine  reaction. 

While  it  is  a  widely  prevalent  belief  that  the  soluble  salts 
of  quinine  are  much  more  rapidly  and  completely  absorbed 
from  the  stomach  than  are  the  insoluble  preparations,  experi- 
ments show  that  such  is  not  the  case. 

Mariani84  records  his  results  as  follows: 


Administered  on  an 

empty  stomach. 

Per  cent. 


Easily  soluble  quinine  salt 36.28 

Hardly  soluble  quinine  salt  45-50 


On  a  full 
stomach. 
Per  cent. 

4445 
68.43 


TREATMENT 


339 


Giemsa  and  Schaumann300  observed  that  the  average  per- 
centage excreted  within  the  first  twenty-four  hours  after  ad- 
ministration of  a  soluble  salt  of  quinine  was  22.9  per  cent., 
while  with  an  insoluble  salt  it  was  24.33  Per  cent.,  and  they 
conclude  that  the  salts  of  quinine,  hardly  soluble  in  water,  are 
at  least  as  energetically  absorbed  from  the  digestive  tract  as 
the  soluble  ones. 

The  results  of  clinical  experience  with  euquinine  and  the 
tannate  of  quinine  fully  support  such  a  conclusion. 

Briquet  and  Quevenne401  formerly  maintained  that  the  ab- 
sorption and  excretion  of  quinine  proceeded  one-sixth  more 
rapidly  in  females  than  in  males.  This  conclusion,  as  yet  un- 
confirmed, should  be  determined  only  after  a  long  series  of 
experiments. 

Employed  hypodermically  the  rapidity  and  thoroughness  of 
absorption  depends  upon  the  solubility  of  the  salt  and  the  con- 
centration of  the  solution.  The  latter  is  of  the  utmost  impor- 
tance, since,  no  matter  how  soluble  the  salt,  if  given  in  strong 
solution  it  will  not  be  absorbed. 

In  order  to  determine  the  effect  upon  human  blood  and 
serum  of  quinine  injections,  Giemsa  and  Schaumann300  added 
to  1  cc.  of  light  red  human  serum  1  cc.  of  solutions  of  different 
strengths  of  various  salts  of  quinine.  Their  results  were  as 
follows : 


Preparation. 


Strength  of 
solution. 


Contents 

equivalent 

to  anhydrous 

quinine       Immediately, 
(per  cent.). 


Sulphate  1 :  160 

Bisulphate  1 :  12 

Hydrochloride    1 :  35 

Bimuriate  1:2 

Birmiriate  with  urea.        1  :  2 

Bisulphate    1.69  :  50 

Hydrochloride    1.22  :  50 

Bimuriate    1.22  :  50 

Bimuriate  with   urea  1.69:  50 


Behavior  of  the  mixture. 

After  twenty-four  hours. 


•45 
4.92 


2-33 

40.8 

29.61 

2.0 
2.0 

2.0 
2.0 


Cloudiness. 
Marked  precipi- 
tation. 

Marked  cloudi- 
ness. 

Clear  coagulum, 
gray    colored. 

Clear  coagulum, 
gray    colored. 

Cloudiness. 

Marked  cloudi- 
ness. 

Cloudiness. 

Cloudiness. 


Precipitation. 

More  decided 
precipitation, 
gray    colored. 

Increased  pre- 
cipitation, co- 
agulation. 

Cloudy  gray  co- 
agulum. 

Cloudy  gray  co- 
agulum. 

Precipitation. 

Precipitation. 

Precipitation. 
Precipitation. 


34°  THE    STUDY    OF    MALARIA 

These  investigators  claim  that  coagulation  and  precipitation 
always  follow  the  injection  of  concentrated  solutions  of  quinine 
into  the  tissues,  and  that  this  accounts  for  the  slower  absorp- 
tion. 

The  rate  of  excretion  after  injection  of  solutions  of  bimuri- 
ate  of  quinine,  i  gram  to  10  cc.  of  water  and  i  gram  to  i  cc. 
of  water,  is  recorded  in  the  following  tables,  respectively: 


Total  daily  elimination  estimated  in  per  cent, 
of  anhydrous  quinine. 

Number  of  patient. 


1:10—  x  *  * 

One  day   21.0  24.1  19.8 

Two  days  26.2  24.9  22.0 

Three  days    _JLJLJL  26.9 

Average    23.6  25.3  20.9 

Average  of  3  cases,  23.3  per  cent. 


1 :  1 — 

One    day    10.3  12.1  8.3 

Two   days    16.3  15.1  5.2 

Three  days    2^2  IM  2-2 

Average    14-9  15-5  5-2 

Average  of  3  cases,  11.8  per  cent. 

Mariani84  found  that  after  the  injection  of  1  gram  of  the 
bimuriate  of  quinine  dissolved  in  10  cc.  of  water  the  maximum 
excretion  occurred  between  the  sixth  and  the  twelfth  hours, 
while  after  the  injection  of  the  same  quantity  of  the  salt  dis- 
solved in  2  cc.  of  water  this  period  occurred  between  the  ninth 
and  the  eighteenth  hours. 

As  compared  with  the  oral  administration  of  quinine  the 
hypodermic  method  has  been  ascertained  to  be  followed  by 
the  absorption  of  a  smaller  proportion  of  the  drug.  The  pro- 
portion is,  according  to  Giemsa  and  Schaumann,300  38.5  :  17.5 ; 
according  to  Mariani,  45.63  :3i.86,  and  according  to  Schmitz,402 
2J.J\  16.1. 

On  account  of  the  fact  that  a  portion  of  the  quinine  injected 
remains  at  the  site  of  injection,  the  period  of  absorption  and 
elimination  extends  over  a  longer  period,  and  the  drug  has 
been  detected  in  the  urine  a  week  or  more  after  injection. 

After  intravenous  administration  quinine  has  been  detected 


TREATMENT  341 

in  the  urine  in  ten  minutes.  In  a  small  series  of  observations 
Mariani84  found  the  average  daily  elimination  after  intrave- 
nous injection  as  follows : 

Per  cent. 

First  day    20.54 

Second  day 6.33 

Third  day i-07 

Injected  into  the  rectum  quinine  appears  in  the  urine  in 
twenty  to  twenty-five  minutes.  On  account  of  the  tenesmus 
which  quinine  solutions  are  prone  to  produce  when  introduced 
into  the  rectum,  experiments  are  not  very  numerous,  but  those 
performed  show  that  the  drug,  even  in  a  highly  soluble  form, 
is  much  less  easily  absorbed  than  when  given  orally. 

Besides  with  the  urine,  quinine  is  excreted  with  the  feces, 
the  milk,  the  sweat,  the  tears,  pathologic  transudates  and  exu- 
dates, the  amniotic  fluid,  and  the  first  urine  of  the  newborn 
children  of  cinchonized  mothers. 

Action  of  Quinine  Upon  the  Malarial  Parasites. — Binz, 
in  1867,  was  the  first  to  assume  that  the  effect  of  quinine  in 
malaria  was  due  to  its  action  as  a  protoplasmic  poison  upon 
the  organisms  which  he  believed  to  be  the  cause  of  the  disease. 
This  conclusion  was  reached  from  a  knowledge  of  the  action 
of  quinine  upon  infusoria. 

In  1 88 1  Laveran  found  that  the  parasites  were  killed  by  the 
addition  of  a  I  :  10,000  solution  of  quinine,  and  concluded  that 
"it  is  because  it  destroys  the  parasites  that  quinine  causes  the 
disappearance  of  the  manifestations  of  paludism." 

Since  the  introduction  of  practical  staining  methods  numer- 
ous observations  upon  the  action  of  quinine  on  the  malarial 
parasites  have  been  made,  of  which  those  of  Craig403  are  espe- 
cially valuable  and  from  which  the  following  is  quoted : 

"The  Tertian  Plasmodium  {Plasmodium  vivax). — The  mor- 
phologic changes  produced  by  quinine  in  the  tertian  Plasmo- 
dium, as  shown  by  stained  specimen,  will  first  be  described. 

"In  order  to  study  these  it  is  necessary  to  give  the  drug  in 
divided  doses  to  single  tertian  infections,  the  first  dose  just 
before  segmentation ;  specimens  of  the  blood  should  then  be 
taken  and  stained  at  intervals  of  every  three  hours  for  the 


342  THE    STUDY    OF    MALARIA 

next  forty-eight  hours.  Given  just  before  segmentation  and 
repeated  at  intervals  of  three  hours,  the  drug  acts  upon  the 
Plasmodia  not  only  while  free  in  the  plasma,  but  also  upon 
every  stage  of  their  human  life  cycle,  and  it  is  thus  possible 
to  study  the  morphologic  changes  produced  by  quinine  in  every 
stage  of  their  development. 

"The  young  'ring  forms'  stain  very  intensely  after  the  ad- 
ministration of  quinine,  the  protoplasm  staining  a  much  darker 
blue  than  normal,  while  the  chromatin  stains  a  dark  crimson. 
Besides  the  increase  in  the  intensity  of  the  stain,  the  only  other 
morphologic  change  observed  is  the  loss  of  the  unstained  area, 
which,  in  normal  specimens,  always  surrounds  the  chromatin. 

"In  tertian  plasmodia  a  little  further  advanced  in  develop- 
ment the  staining  reactions  are  the  same  as  in  the  'ring  forms,' 
but  the  increased  motility  of  the  parasites  is  shown  in  the  great 
number  and  the  'bizarre'  arrangement  of  the  pseudopodia. 
Fragmentation  is  observed  even  before  the  formation  of  pig- 
ment, some  of  the  plasmodia  at  this  stage  being  broken  up 
into  deeply  stained  portions,  the  chromatin  lying  in  one  of 
these  portions  or  free  near  the  periphery  of  the  erythrocyte. 

"After  the  formation  of  pigment,  and  especially  after  the 
plasmodia  are  from  one-half  to  three-quarters  grown,  the  evi- 
dence of  fragmentation  and  of  extrusion  of  the  chromatin 
from  the  parasite  become  more  marked.  Many  of  the  erythro- 
cytes contained  portions  of  deeply  stained  protoplasm,  the  chro- 
matin of  the  plasmodium  lying  free  at  some  portion  of  the 
red  cell.  The  latter  is  often  situated  at  the  extreme  periphery 
or  partly  outside  of  the  erythrocyte. 

"At  this  stage  numerous  extracellular  plasmodia  are  seen, 
either  undergoing  fragmentation  or  hydropic  degeneration. 
Many  of  the  fragments  are  entirely  devoid  of  pigment,  stain- 
ing a  uniform  deep  blue  throughout,  while  some  may  be  almost 
filled  with  pigment  granules.  The  unstained  area  about  the 
chromatin  is  always  absent,  nor  is  there  any  indication  of  an 
increase  in  the  amount  of  chromatin  which  is  so  noticeable 
in  the  normal  plasmodia  at  this  stage. 

"While  at  this  stage  many  fragmented  plasmodia  are  usually 
observed,   in  some  instances  no  evidence  of  this  process  is 


TREATMENT  343 

seen.  The  protoplasm  stains  a  uniform  dark  blue,  the  pigment 
being  collected,  as  a  rule,  about  the  periphery,  while  the  chro- 
matin stains  intensely  and  may  be  situated  at  any  portion  of 
the  organism,  but  usually  near  the  periphery.  There  is  no 
unstained  area  surrounding  the  chromatin. 

"In  many  instances  the  chromatin  is  situated  at  the  extreme 
periphery  of  the  plasmodium  or  may  lie  partly  or  wholly  out- 
side of  it  within  the  erythrocyte,  thus  proving  that  quinine 
possesses  the  power  of  causing  extrusion  of  the  chromatin, 
thus  rendering  the  plasmodium  sterile. 

"Together  with  the  absence  of  the  vesicular  portion  of  the 
nucleus,  as  shown  by  the  loss  of  the  unstained  area  surround- 
ing the  chromatin,  there  is  but  seldom,  even  in  those  organisms 
which  are  not  undergoing  fragmentation,  any  evidence  of  in- 
crease of  the  chromatin,  and  never  any  evidence  of  its  division. 

"When  the  tertian  plasmodium  is  nearly  full  grown  quinine 
very  often  causes  fragmentation,  many  of  the  fragmentated 
organisms  being  free  from  chromatin,  but  the  characteristic 
change  from  the  normal  at  this  stage  of  growth  consists  in 
the  fact  that,  although  the  chromatin  may  be  present  and  stain 
very  intensely,  it  has  increased  but  little  or  not  at  all  in  amount, 
and  division  is  either  absent  or  imperfect,  only  two  or  three 
small  masses  being  present,  which  lie  close  together  near  the 
periphery  of  the  organism.  In  tertian  plasmodia  which  have 
not  been  influenced  by  quinine  and  have  reached  this  stage  of 
development,  the  chromatin  has  always  increased  largely  in 
amount  and  divided  into  several  small  clumps,  which  are  scat- 
tered throughout  the  organism.  The  morphology  of  the  plas- 
modia at  this  period  of  their  growth  indicates  clearly  that 
quinine  prevents  an  increase  in  the  amount  of  the  chromatin, 
and  either  hinders  division  or  stops  it  altogether. 

"At  this  stage  the  protoplasm  of  the  organism  stains  deeply, 
and  the  pigment  is  collected  about  the  periphery  in  blocks  or 
granules,  or  distributed  throughout  the  protoplasm  in  the  form 
of  fine  granules  or  small  clumps. 

"The  unstained  area  about  the  chromatin  is  always  absent. 
Those  plasmodia  which  sporulate  after  being  exposed  to  the 
action  of  the  quinine  throughout  their  entire  cycle  of  develop- 


344  THE   STUDY   OF   MALARIA 

ment  present  very  marked  morphologic  evidences  of  the  inju- 
rious effect  of  the  drug.  While  sporulation  may  not  be  entirely 
prevented,  the  majority  of  the  spores  are  devoid  of  chromatin 
and  are  undoubtedly  sterile.  The  segments  are  also  decreased 
in  number  and  may  be  distorted  in  shape,  while  in  the  seg- 
ments which  show  the  presence  of  chromatin  the  latter  is  in  the 
form  of  irregular  masses,  very  distinct  from  the  usual  form 
as  seen  in  normal  plasmodia.  Very  often  sporulating  bodies 
are  observed  in  which  only  two  or  three  of  the  segments  pos- 
sess chromatin ;  in  such  segments  the  protoplasm  stains  a  deep 
blue  and  there  is  no  unstained  area  surrounding  the  chromatin. 

"Associated  with  the  chromatin  containing  segments  are 
from  six  to  eight,  or  perhaps  more,  deeply  stained  segments 
containing  no  chromatin. 

"In  the  segmenting  plasmodia  the  pigment,  instead  of  being 
collected  in  a  dense,  compact  mass,  as  is  the  rule  in  the  normal 
tertian  plasmodia,  is  reduced  in  amount  and  scattered  in  small 
clumps  or  granules  between  the  segments. 

"From  the  morphologic  changes  described  it  is  evident  that 
quinine,  administered  in  divided  doses,  exercises  a  markedly 
injurious  effect  upon  every  stage  in  the  human  life  cycle  of 
the  tertian  plasmodium,  either  causing  the  death  of  the  organ- 
ism at  some  period  of  its  development  or  preventing  normal 
sporulation  by  restraining  the  division  of  the  chromatin  prior 
to  segmentation.  The  death  of  the  organism  is  evidenced  by 
fragmentation  or  the  extrusion  of  the  chromatin,  while  the 
effect  upon  sporulation  is  shown  by  the  limited  division  of 
the  chromatin  and  the  large  number  of  segments  which  are 
devoid  of  this  essential  portion  of  the  nucleus. 

"If  quinine  is  administered  in  one  large  dose,  which  is  not 
repeated,  at  any  stage  of  the  development  of  the  tertian  Plas- 
modium prior  to  segmentation,  the  changes  produced  are.  the 
same  in  kind  as  those  already  described,  but  a  comparatively 
large  number  escape  entirely  or  are  but  little  injured. 

"When  quinine  is  administered  just  prior  to  segmentation  it 
does  not,  as  has  been  maintained  by  numerous  authorities, 
prevent  segmentation,  nor  do  the  stained  preparations  show 
any  distinct  morphologic  changes  in  the  segmenting  bodies. 


TREATMENT  345 

"The  Quartan  Plasmodium  {Plasmodium  malaria:). — The 
changes  produced  by  quinine  in  the  quartan  plasmodium,  as 
shown  by  stained  preparations,  are  the  same  as  those  described 
for  the  tertian  plasmodium,  and  I  cannot  agree  with  Golgi 
and  Antolisei  that  upon  the  adult  plasmodium  the  drug  has  no 
effect.  I  have  not  been  able  to  observe  any  difference,  so  far 
as  morphologic  evidence  goes,  in  the  effect  of  quinine  upon  the 
tertian  and  quartan  plasmodia,  although  it  is  undoubtedly  true 
that,  because  of  greater  resistance  to  the  drug,  a  larger  number 
of  quartan  plasmodia  escape  destruction  at  the  time  of  sporu- 
lation. 

"The  Estivo-autumnal  Plasmodia  {Plasmodium  immacu- 
latum). — I  have  not  been  able  as  yet  to  study  the  effect  of 
quinine  upon  the  full-grown  or  segmenting  estivo-autumnal 
plasmodia,  but  have  studied  many  specimens  containing  the 
'ring  forms'  and  the  young  pigmented  forms.  The  results  of 
my  observations  are  opposed  to  those  of  Marchiafava  and 
Bignami,  who  claim  that  no  morphologic  changes  are  produced 
in  these  plasmodia  by  the  drug,  and  that  the  unpigmented  para- 
sites do  not  become  pigmented  after  its  administration.  I 
have  repeatedly  seen  pigmented  forms  of  both  the  tertian  and 
the  quotidian  estivo-autumnal  plasmodia  develop  after  quinine 
had  been  administered  for  as  long  as  three  days,  while  the 
morphologic  changes  produced  are  similar,  but  not  as  marked 
as  those  observed  in  the  tertian  and  quartan  plasmodia. 

"In  the  'ring  forms,'  which  are  most  easily  studied,  the 
staining  capacity  of  both  the  chromatin  and  the  protoplasm  is 
increased,  but  the  unstained  area  surrounding  the  chromatin 
disappears.  A  large  number  of  the  'ring  forms'  may  appear 
normal,  but  careful  examination  will  always  show  that  numer- 
ous parasites  show  the  loss  of  the  unstained  area  and  the 
'rings'  are  distorted  in  shape  owing  to  increased  ameboid 
movement.  In  a  few  instances  I  have  observed  the  separation 
of  the  chromatin  from  the  body  of  the  plasmodium,  thus  show- 
ing that  extrusion  had  occurred.  I  have  never  observed  frag- 
mentation of  the  'ring  forms.' 

"The  changes  produced  in  the  young  pigmented  estivo- 
autumnal  plasmodia  are  similar  in  every  respect  to  those  occur- 


346  THE   STUDY   OF   MALARIA 

ring  in  the  tertian  and  quartan  plasmodia,  consisting  in  frag- 
mentation, loss  of  the  unstained  area  surrounding  the  chro- 
matin, and  extrusion  of  the  chromatin." 

It  is  well  known  that  the  sexual  forms  of  the  malarial  para- 
sites are  very  resistant  to  quinine,  persisting  in  the  blood  for 
weeks  and  months  despite  the  liberal  use  of  quinine. 

While  young  and  half -grown  tertian  and  quartan  gametes 
are  sometimes  destroyed  by  quinine,  those  of  the  estivo- 
autumnal  variety  are  exceedingly  difficult  to  kill.  In  fact,  it 
has  been  maintained  that  the  administration  of  quinine  to 
patients  harboring  only  the  asexual  forms  favors  the  develop- 
ment of  crescents. 

Schaudinn134  infected  anopheles  mosquitoes  with  tertian 
gametes  from  the  blood  of  his  servant  girl,  who  had  been 
taking  a  gram  of  quinine  three  times  weekly  for  a  month. 

Gualdi  and  Martirano150  arrived  at  the  following  conclusions 
with  respect  to  the  effect  of  quinine  upon  crescents : 

i.  Quinine  administered  in  a  single  dose  of  2.50  grams  or  of 
1. 00  to  1.50  grams  for  many  consecutive  days  is  not  able  to 
cause  the  disappearance  of  crescents  from  the  blood. 

2.  Quinine  in  doses  sufficient  to  destroy  ameboid  forms  of 
the  parasite  not  only  do  not  destroy  the  crescents,  but  do  not 
inhibit  their  development  within  the  body  of  the  mosquito. 

3.  Quinine  does  not  appreciably  shorten  the  period  during 
which  crescents  remain  in  the  blood  after  the  cessation  of  fever, 
the  period  which  represents  the  contagious  term  of  the  disease. 

Macrogametes  are  more  resistant  to  the  effects  of  quinine 
than  are  the  microgametocytes.  This  may  possibly  be  due  to 
the  thicker  protoplasmic  body  of  the  former,  and  explains  the 
difficulty  of  interrupting  the  parthenogenetic  cycle,  the  cycle 
of  chronic  or  latent  malaria. 

Binz  observed  that  infusoria  were  stimulated  to  increased 
movement  by  quinine.  The  same  has  been  noted  with  the 
parasites  of  malaria. 

According  to  Mannaberg,404  a  short  time  after  the  adminis- 
tration of  quinine  medium-sized  tertian  parasites  are  often 
observed  in  very  active,  even  convulsive,  movement,  from 
which  it  appears  that  the  parasites  are  at  first  irritated  to 


TREATMENT  347 

increased  movement.  Bacelli131  observed  the  same  in  quar- 
tan parasites. 

Cohen305  believes  this  action  of  quinine  to  be  useful  in  diag- 
nosis. He  states  that  in  cases  of  doubtful  diagnosis  the  injec- 
tion of  a  quantity  of  the  drug  not  sufficient  to  insure  a  definite 
freedom  period  will  frequently  cause  the  appearance  in  the 
peripheral  blood  of  organisms  recognizable  as  normal  or  atypic 
forms  of  the  hemameba  of  malaria,  and  this  has  been  observed 
so  frequently  and  in  so  many  diverse  conditions  that  he  is 
inclined  to  look  upon  its  absence  after,  say,  half  a  dozen  injec- 
tions, varying  from  three  days  to  a  week  apart  and  in  doses 
increasing  from  0.3  to  1  gram,  as  virtually  excluding  malarial 
infection.  He  is  of  the  opinion  that  in  such  cases  the  organism 
is  resting  in  some  larval  form,  probably  in  the  spleen  or  bone- 
marrow,  and  that  its  appearance  peripherally  is  part  of  a  de- 
fensive, reproductive  reaction  to  the  paratoxic  effect  of  quinine. 

That  small  doses  of  quinine  are  able  to  arouse  latent  malaria 
is,  in  the  writer's  opinion,  unquestionable.  This  can  only  be 
explained  satisfactorily  by  assuming  that  quinine  stimulates 
the  parthenogametes  into  a  compensatory  reproduction. 

The  relation  of  the  time  when  the  quinine  is  administered 
to  the  temperature  curve  and  the  behavior  of  the  parasites  has 
been  carefully  studied  by  Marchiafava  and  Bignami,22  the  re- 
sults of  whose  observations  may  be  summarized  as  fol- 
lows : 

1.  If  the  quinine  is  administered  during  the  crisis  of  an 
attack  and  continued  during  the  apyrexia,  which  follows  in  the 
majority  of  cases,  the  next  expected  attack  is  inhibited  or 
there  is  merely  a  slight  elevation  of  temperature,  with  a  slight 
sense  of  discomfort.  In  a  smaller  number  of  cases,  even  when 
strong  doses  of  quinine  are  given  during  the  crisis  and  the 
period  of  apyrexia,  the  attack  is  not  prevented,  but  is  delayed 
and  abortive. 

2.  If  quinine  in  the  usual  dose  is  administered  within  the 
six  hours  preceding  the  expected  attack  it  may  have  no  influ- 
ence at  all  upon  the  temperature  of  the  succeeding  paroxysm. 
In  other  cases  there  is  noticed  a  slight  delay  in  the  attack, 
which  also  is  less  severe  than  the  preceding  one,  but  even  in 


34^  THE    STUDY   OF   MALARIA 

this  case  the  temperature  curve  is  the  typic  one  of  an  estival 
tertian.     Subsequent  attacks,  as  a  rule,  do  not  occur. 

3.  If  the  remedy  is  administered  at  the  onset  of  the  attack 
in  the  majority  of  cases  the  attack  will  come  on  in  the  usual 
way,  and  may  even  be  grave  and  prolonged ;  very  often,  how- 
ever, there  are  some  modifications  in  the  curve.  A  subsequent 
attack  does  not  usually  occur,  although  there  may  be  frequent 
irregular  elevations  of  temperature. 

4.  When  the  quinine  is  given  during  the  febrile  attack  be- 
ginning shortly  after  the  onset  and  continuing  throughout  the 
course  of  the  fever  in  a  series  of  cases  the  characteristic  curve 
of  the  tertian  is  not  appreciably  modified,  while  in  another 
series  there  are  various  modifications.  In  a  whole  series  of 
cases  when  the  quinine  has  been  given  in  large  amount  during 
the  attack,  there  are  apt  to  be  no  subsequent  attacks,  or  on  the 
following  day  or  days  there  are  only  slight  elevations  of  tem- 
perature. 

5.  If  quinine  is  given  near  the  time  of  the  crisis  when  the 
blood  contains  only  young  non-pigmented  parasites,  and  if 
its  administration  is  continued  for  about  twelve  hours,  the 
parasites  continue  to  be  seen  in  the  peripheral  blood  for 
nearly  twenty-four  hours,  together  with  pigmented  leuko- 
cytes. 

6.  If  quinine  is  given  in  the  last  hours  preceding  the  attack, 
when  the  only  bodies  found  in  the  blood  are  the  pigmented 
adult  parasites,  or  these  predominate,  then  the  parasites  go 
on  to  their  development  up  to  fission,  but  the  new  generation, 
as  a  rule,  does  not  present  itself  in  the  following  attack.  In 
other  cases,  while  we  do  not  see  the  generation  of  young  para- 
sites, we  have  bodies  belonging  to  the  crescent  group ;  it  would 
appear  that  in  this  case  the  parasites,  instead  of  going  on  to 
sporulation,  take  the  other  road  which  leads  to  the  formation  of 
crescent  forms. 

7.  When  the  remedy  is  given  at  the  beginning  of  the  attack, 
at  the  time  when  in  the  blood  we  find  fission  forms,  or  those 
that  have  already  become  divided,  the  action  of  the  remedy 
is  subsequently  recognized  by  the  fact  that  the  ameba  of  the 
new  generation  become  extremely  scarce,  and  if  the  quinine  be 


TREATMENT  349 

continued  they  disappear  entirely  from  the  blood  within  the 
twenty-four  hours. 

It  is  the  uniform  result  of  experience  that  the  stage  of  the 
parasite  most  susceptible  to  the  action  of  quinine  is  the  mero- 
zoite,  the  spore  before  it  has  assumed  the  protection  of  the 
red  cell.  Hence  it  is  desirable  to  have  in  the  blood  as  strong 
a  solution  of  quinine  as  possible  at  the  time  of  sporulation,  that 
the  young  parasites  may  be  born  into  a  toxic  medium. 

The  exact  manner  in  which  quinine  destroys  the  parasite  of 
malaria  is  not  certain.  Whether  it  acts  as  a  direct  poison  to 
the  parasite,  or  by  stimulating  phagocytosis,  or  by  increasing 
the  fluorescence  of  the  blood,  or  by  forming  indigestible 
combinations  with  the  blood  elements  has  not  been  deter- 
mined. 

Golgi's131  scale  of  susceptibility  of  the  parasites  to  quinine, 
with  reference  to  the  variety  of  the  parasite,  is,  I,  tertian;  2, 
quartan,  and,  3,  estivo-autumnal ;  and,  with  reference  to  the 
stage  of  the  parasite,  1,  spores;  2,  mature  forms  before  begin- 
ning sporulation;  3,  endoglobular  young  forms. 

Some  Effects  of  Quinine  Upon  the  Human  Organism. 
— Quinine  is  one  of  the  few  drugs  possessed  of  great  thera- 
peutic power  which  has  relatively  little  toxic  property;  never- 
theless, in  exceptional  instances,  untoward  effects  result  from 
its  use.  Reference  is  not  made  to  the  group  of  symptoms 
known  as  cinchonism,  ringing  in  the  ears,  slight  deafness,  roar- 
ing, the  fulness  in  the  head,  dizziness,  nervousness,  a  bitter 
taste,  and  slight  nausea.  But  manifestations  of  a  more  serious 
nature  occasionally  arise. 

Practitioners  are  very  often  told  by  patients  that  they  cannot 
take  quinine.  The  writer  has  made  it  a  rule  to  disregard 
such  statements  and  to  administer  quinine  where  indicated, 
disguised  if  need  be,  and  in  only  two  instances  has  he  had  cause 
for  regret. 

One  case  was  that  of  a  rather  nervous  woman  in  whom 
3  grains  of  the  bimuriate  of  quinine,  given  orally,  produced 
within  half  an  hour  distressing  urticaria  and  nervousness,  and 
alarming  dyspnea  and  depression  which  lasted  for  several 
hours.    There  was  no  lesion  of  the  heart  or  other  organs.   This 


35°  THE    STUDY    OF    MALARIA 

same  effect  had  several  times  formerly  resulted  from  small 
doses  of  quinine. 

The  other  case  was  that  of  a  woman  with  a  mitral  regurgi- 
tant murmur,  who  stated  that  every  time  in  her  life  that  quinine 
had  been  given  her  she  thought  she  would  die  of  suffocation. 
Three  grains  of  euquinine  in  powder  were  given  her,  and  in 
a  short  time  she  was  prostrated,  suffering  with  severe  dyspnea 
and  fear  of  death.    These  symptoms  lasted  about  an  hour. 

Gudden405  observed  in  several  patients  as  a  result  of  I  gram 
of  quinine,  headache,  nausea,  vomiting,  a  sense  of  burning  heat, 
a  chill,  and  elevation  of  temperature  to  102.2°  F..  and  pulse  to 
164.     The  urine  contained  no  albumin. 

Plehn406  records  a  case  of  a  woman  who,  a  few  minutes  after 
taking  x/2  gram  of  quinine,  was  seized  with  itching  of  the 
skin,  an  erythematous  rash  upon  the  neck  and  breast,  a  chill, 
and  rise  of  fever  to  102°  F.  After  the  intramuscular  injection 
of  1  gram  of  quinine  the  temperature  became  104°  F.  The 
urine  was  normal  and  the  elevation  of  temperature  lasted  only 
a  few  hours. 

Trousseau  and  Pidoux86  report  the  case  of  a  patient  who 
took  at  one  dose  3  grams  of  quinine  for  the  cure  of  asthma, 
which  recurred  every  day  at  a  certain  hour.  Four  hours  later 
he  experienced  ringing  in  the  ears,  dizziness,  and  terrific  vomit- 
ing. Seven  hours  after  taking  the  drug  he  was  blind  and  deaf, 
delirious,  and  unable  to  walk  on  account  of  vertigo.  He  was 
vomiting  constantly.  These  symptoms  ceded  spontaneously 
during  the  middle  of  the  night. 

Grenier407  cites  the  example  of  a  girl  of  fifteen  years  who 
took  a  moderate  dose  of  quinine  for  an  attack  of  fever.  A 
short  time  later  she  had  nausea,  vertigo,  deafness,  visual  dis- 
turbances, swelling  of  the  face,  dyspnea,  profound  prostration, 
general  urticaria,  edema  of  the  hands  and  feet,  and  vomiting. 
These  symptoms  disappeared  in  the  course  of  six  hours,  but 
returned  each  time  even  a  small  dose  of  quinine  was  given, 
even  though  unrecognized. 

Large  doses  of  quinine  may  even  prove  fatal.  Laveran1 
speaks  of  two  soldiers,  intending  to  take  sulphate  of  soda  as 
a  purgative,  took  by  mistake  12  grams  each  of  quinine.     In 


TREATMENT  35 1 

half  an  hour  they  were  taken  with  cramping  in  the  stomach, 
vomiting,  facial  pallor,  dilatation  of  the  pupils,  superficial  res- 
piration, chilliness ;  pulse  small,  irregular,  sometimes  insensible, 
and  a  tendency  to  syncope.  One  of  the  patients  recovered,  the 
other  died  in  collapse. 

Quill408  reports  the  case  of  a  patient  who  took  ^2  ounce 
of  the  sulphate  of  quinine.  Toxic  symptoms  appeared  within 
two  minutes;  these  were  retching  and  vomiting,  unconscious- 
ness, slow  and  labored  respiration,  a  barely  perceptible  pulse, 
convulsions,  affecting  chiefly  the  lower  extremities.  Death  fol- 
lowed soon. 

Numerous  other  cases  of  quinine  poisoning  could  be  cited. 
The  symptoms  most  frequently  recorded  are  headache,  de- 
lirium, muscular  weakness,  staggering  gait,  dyspnea,  collapse, 
deafness,  amaurosis,  psychic  disturbance,  cutaneous  eruptions, 
hemorrhages,  and  fever. 

Fever  caused  by  quinine  was  recognized  as  early  as  1790 
by  Hahnemann.409  He  says :  "For  experiment's  sake,  I  took 
60  grains  of  cinchona  bark  twice  daily  for  a  few  consecutive 
days ;  my  feet  and  hands  became  cold,  followed  by  a  feeling  of 
malaise,  palpitation  of  the  heart,  pulse  hard  and  rapid,  a  feel- 
ing of  apprehension,  then  a  beating  headache,  flushing  of  the 
cheeks,  thirst,  and  all  the  usual  symptoms  of  intermittent  fever. 
These  symptoms  lasted  two  to  three  hours  each  time  and  re- 
turned after  each  dose.  I  stopped  the  bark  and  I  was 
healthy." 

Numerous  cases  have  since  been  observed.  F.  Plehn,5  who 
had  a  number  of  cases,  believes  that,  while  it  appears  more 
often  in  tropic  than  in  temperate  climates,  it  may  occur  in  those 
who  have  never  suffered  with  malaria,  and  occurs  oftener  in 
old  residents  than  in  newcomers.  The  fever  may  be  preceded 
by  a  chill,  is  accompanied  with  other  evidences  of  cinchonism, 
and  is  sometimes  associated  with  the  cutaneous  manifestations 
of  quinine. 

For  the  report  of  a  case  in  this  country,  with  an  interesting 
review  of  the  literature  and  a  bibliography,  the  reader  is  re- 
ferred to  the  article  of  Goodman.409     This  writer  believes  the 


352  THE    STUDY   OF    MALARIA 

explanation  of  this  untoward  effect  of  quinine  to  be  that  some 
chemic  changes  in  the  blood  act  on  the  heat-dissipating  appa- 
ratus in  persons  who  have,  or  have  had,  malaria. 

The  condition  is  as  yet  too  obscure  to  warrant  any  conclu- 
sions. A  careful  study  of  the  blood  might  reveal  the  patho- 
genesis. .  Some  cases  probably  bear  an  analogy  to  the  condi- 
tion produced  by  quinine  in  certain  persons  whom  Koch 
designates  "blackwater-fever  candidates." 

Quinine  in  large  doses  is  undoubtedly  somewhat  depressing 
to  the  heart,  as  exemplified  in  some  of  the  cases  recited.  It 
may  cause  syncope,  or  even  collapse  and  death.  In  fatal  cases 
the  heart  is  said  to  be  arrested  in  diastole. 

Quinine  may  cause  temporary  psychic  disturbance,  even  in- 
sanity and  delirium.  The  latter  occurs  either  in  an  active, 
noisy  form,  with  loquacity  and  agitation,  or  in  a  quiet  form, 
with  stupor  and  depression. 

The  chief  digestive  disorders  referable  to  quinine  are  nausea, 
vomiting,  anorexia,  and  gastric  and  intestinal  catarrh.  Gastric 
and  intestinal  hemorrhages  have  been  attributed  to  the  use 
of  the  drug,  as  well  as  hemorrhages  from  the  mouth,  gums, 
nose,  lungs,  skin,  and  conjunctiva. 

The  cutaneous  eruptions  of  quinine  origin  may  be  caused  by 
small  doses.  They  are  most  apt  to  follow  the  administration 
of  the  sulphate.  The  writer  has  seen  persons  in  whom  the 
sulphate  had  always  produced  annoying  urticaria,  take  the 
bimuriate  with  no  untoward  effect.  The  pruritus  attending 
some  of  these  eruptions  is  sometimes  agonizing,  the  patients 
declaring  that  the  remedy  is  worse  than  the  disease. 

It  is  said  that  laborers  in  the  manufacture  of  quinine  often 
experience  pruritus  of  the  hands  and  forearms,  followed  by 
redness  and  a  lichenoid  eruption,  sometimes  with  swelling  of 
the  face  and  genitals. 

Urticaria  is,  in  the  experience  of  the  writer,  the  most  fre- 
quent of  these  manifestations.  It  may  be  general  or  quite 
local,  and  is  sometimes  attended  with  edema  of  the  face  and 
hands.  The  writer  has  seen  only  one  such  case  in  the  negro 
race. 

Erythema,  scarlatinal  or  morbilliform  in  appearance,  is  some- 


TREATMENT 


353 


times  observed.     It  may  be   followed  by  desquamation  and 
prove  difficult  of  diagnosis. 

Vesicular  eruptions  are  but  rarely  seen  as  the  result  of 
quinine  administration.  Petechias  are  occasionally  noted,  and 
Kulz90  has  reported  a  case  of  purpura  hemorrhagica  referable 
to  i  gram  of  quinine.  The  hemorrhages  proceeded  from  the 
stomach,  intestines,  mouth,  nose,  skin,  and  conjunctiva.  The 
entire  skin  was  covered  with  petechias  from  the  size  of  a  lentil 
to  that  of  a  dollar.  Even  the  pinching  between  the  fingers  of 
a  fold  of  skin  resulted  in  a  purpuric  spot.  Quantities  of  blood 
were  vomited  and  purged.  The  temperature  remained  normal 
and  the  general  condition  was  surprisingly  little  disturbed. 
Under  rest,  opium,  diet,  and  tamponning  of  the  gums  the 
hemorrhages  ceased  upon  the  first  day.  Eight  days  later  the 
administration  of  .05  gram  of  euquinine  was  followed  in  three 
hours  by  similar  symptoms.  Afterward  an  injection  of  quinine 
precipitated  an  attack  of  hemoglobinuria,  which  terminated  in 
recovery. 

The  pathogenesis  of  these  skin  lesions  is  not  clearly  under- 
stood, but  it  is  probable  that  they  are  produced  by  some  action 
of  the  drug  upon  the  skin  in  its  elimination  through  the  sweat 
glands. 

Considering  the  fact  that  quinine  is  in  great  part  eliminated 
by  the  urinary  organs,  these  organs  suffer  but  few  untoward 
effects.  The  drug  has  only  a  slight  diuretic  action.  Albu- 
minuria has  been  observed  following  the  administration  of  the 
drug  to  malarial  subjects,  but  whether  this  was  due  to  the 
drug  or  to  the  disease  is  questionable.  Cases  of  so-called 
hematuria  have  been  reported  as  a  result,  but  many  of  these 
cases  were  undoubtedly  hemoglobinuria,  the  result  of  hemolysis 
rather  than  of  local  irritation. 

The  role  of  quinine  in  the  production  of  hemoglobinuria  has 
been  considered. 

Uterine  colic  may  result  from  quinine,  and  the  writer  has 
seen  several  instances  of  metrorrhagia  and  menorrhagia. 

Inasmuch  as  abortion  not  infrequently  occurs  in  the  course 
of  malarial  fever  treated  with  quinine,  this  effect  is  often  at- 
tributed to  the  drug.     While  quinine  undoubtedly  strengthens 

23 


354  THE    STUDY   OF    MALARIA 

preexisting  uterine  contractions,  it  is  extremely  doubtful 
whether  it  initiates  labor  pains  except  in  a  very  limited  number 
of  cases.  The  writer  has  several  times  seen  patients  threatened 
with  miscarriage  whose  pains  were  promptly  quieted  by  the 
immediate  administration  of  quinine,  and  he  believes  that  abor- 
tion in  these  cases  is  oftener  due  to  too  little  quinine  than  to 
too  much.  Pregnant  women  may  take  quinine  prophylactically 
for  long  periods,  and  if  they  keep  free  from  malaria  they  show 
no  tendency  to  abort. 

The  effect  of  quinine  upon  the  eye  is  sometimes  a  matter 
of  much  concern.  Total  blindness  may  result,  but  fortunately 
this  severe  degree  does  not  last  long,  though  some  constriction 
of  the  visual  field  may  persist  permanently.  Quinine  ambly- 
opia is  usually  accompanied  by  other  toxic  effects,  being  due 
ordinarily  to  large  doses  of  the  drug  continued  for  several 
days.  The  condition  is  usually  bilateral  and  attended  with 
photophobia,  dilated  pupils,  diminished  pupillary  reaction,  color 
blindness,  concentric  restriction  of  the  visual  field,  retinal 
anemia,  with  vascular  constriction  and  atrophy  of  the  optic 
nerve.  DeSchweinitz  found  quinine  and  urea  more  toxic  with 
reference  to  the  eye  than  any  other  preparation  he  employed. 
The  prognosis  is  usually  good,  normal  vision  being  entirely 
regained  in  the  majority  of  cases,  but  the  condition  may  per- 
sist for  months.  The  differentiation  of  this  condition  from 
malarial  amaurosis  has  been  considered. 

Tinnitus  and  a  degree  of  deafness  are  common  results  of 
quinine.  The  deafness  may  be  temporarily  complete.  Con- 
gestion of  the  malleolus,  with  opacity  and  retraction  of  the 
drum,  are  the  common  conditions  present. 

The  action  of  quinine  on  the  spleen  is  doubtful.  While 
Catani,410  Rochfontaine,410  Herrlich,409  and  Piorry86  maintain 
that  it  causes  a  contraction,  even  of  the  healthy  organ,  their 
results  could  not  be  confirmed  by  Valleix  and  Briquet.86 

The  behavior  of  the  leukocytes  under  the  influence  of  quinine 
is  disputed.  Vincent  and  Bastianelli86  observed  that  the  ad- 
ministration of  quinine  caused  an  increase  in  the  number  of 
mononuclear  leukocytes.  Billet86  noted  that  within  three  to  five 
hours  after  administration  there  occurred  a  diminution  of  the 


TREATMENT  355 

leukocytes,  and  in  ten  or  twelve  hours  a  mononuclear  increase, 
even  greater  than  the  average  for  untreated  malaria. 

Binz  maintained  that  quinine  interfered  with  the  movements 
of  the  leukocytes  and  with  diapedesis,  but  Hayem  was  unable 
to  verify  these  observations. 

Marchiafava  and  Bignami162  observed  a  remarkable  develop- 
ment in  the  phagocyte  phenomena  after  the  administration 
of  the  salts  of  quinine,  but  believed  that  it  was  not  due  to  an 
increase  in  the  phagocyte  energy  brought  about  by  the  drug, 
but  to  the  greater  quantity  of  necrotic  forms,  and  of  free 
pigment,  which  is  diffused  in  the  blood  in  consequence  of  the 
direct  action  of  the  remedy  on  the  parasites,  the  phagocytes 
removing  the  dead  forms  which  render  the  blood  impure.  All 
that  these  writers  could  say  with  certainty  was,  that  the  salts 
of  quinine  do  not  hinder  the  phagocyte  activity  of  the  white 
blood  corpuscles,  nor  is  their  mobility  modified. 

Disselhorst  and  others233  proved  by  experiments  upon  frogs 
that  the  motility  and  the  phagocyte  function  of  the  leukocytes 
is  unimpaired  by  quinine.  Mannaberg404  considered  that  the 
phagocytes  in  the  internal  organs  have  their  functions  rather 
weakened  than  stimulated  by  quinine. 

Contra-indications  to  the  Use  of  Quinine. — The  mere  state- 
ment of  the  patient  that  he  is  unable  to  take  quinine  should 
constitute  no  bar  to  the  use  of  the  specific.  The  history  of  the 
invariable  sequence  of  very  severe  skin  manifestations  should 
perhaps  lead  the  physician  to  employ  one  of  the  substitutes  for 
quinine. 

Cardiac  depression  and  dyspnea  are  a  decided  contra-indica- 
tion  to  the  administration  of  the  drug. 

The  treatment  of  malaria  complicating  pregnancy  is  essen- 
tially the  same  as  under  other  conditions.  A  fear,  probably 
more  fancied  than  real,  of  the  oxytocic  properties  of  quinine  is 
widely  prevalent,  but  of  the  dilemma,  malaria  or  quinine,  the 
latter  is  certainly  the  shorter  horn.  The  pregnant  patient  runs 
far  less  risk  of  abortion  with  rational  quinine  treatment  than 
without.  Malaria  during  pregnane)'-  is  notoriously  stubborn, 
and,  while  the  attack  should  be  treated  with  the  smallest  doses 
necessary  to  effect  a  prompt  cure,  systematic  and  prolonged 


356  THE   STUDY   OF    MALARIA 

quinine  prophylaxis  is  necessary  to  prevent  recurrences.  If 
labor  pains  have  begun  opium  should  be  administered  with  the 
quinine. 

The  history  of  hemoglobinuric  fever  is  no  contra-indication 
to  the  use  of  quinine.  While  the  administration  of  the  drug  is 
sometimes  the  occasion  of  an  outbreak  of  blackwater  fever,  the 
latter  is  generally  due  to  too  little  quinine  rather  than  to  too 
much.  Nor  is  it  advisable  to  restrict  the  size  of  the  dose 
unnecessarily  through  fear  of  an  attack,  since  it  has  been  shown 
that  the  amount  of  quinine  is  of  little  importance  in  the  eti- 
ology, very  small  quantities  being  as  prone  to  occasion  the 
attack  as  moderate  amounts. 

Choice  of  Preparation. — This  is  influenced  by  the  age  of 
the  patient,  the  mode  of  administration,  the  severity  of  the 
attack,  and  other  factors. 

The  sulphate,  on  account  of  its  cheapness  and  ease  with 
which  it  is  obtained,  is  widely  employed.  The  writer,  however, 
now  rarely  employs  it,  and  then  only  in  suspension  in  syrup  of 
yerba  santa  for  children.  It  is  probable  that  it  gives  rise  to 
more  gastro-intestinal  and  nervous  disturbances  than  any  other 
salt  of  quinine,  and  it  is  these  manifestations  produced,  as  a 
rule,  by  this  salt  which  cause  so  many  persons  to  say  to  the 
physician  that  they  cannot  take  quinine. 

The  bisulphate,  the  hydrobromide  or  bromide,  and  the  hydro- 
chloride are  useful  preparations,  being  easily  dissolved  and 
readily  absorbed. 

The  bimuriate,  or  acid  hydrochloride,  or  bihydrochlorate  is 
the  most  valuable  salt  of  quinine.  Its  great  solubility  adapts  it 
for  solution  to  be  given  by  mouth,  by  rectum,  intramuscularly, 
or  intravenously. 

Euquinine,  or  quinine  ethyl  carbonate,  has  been  thoroughly 
tried  and  has  given  satisfactory  results  in  the  writer's  hands. 
Being  practically  tasteless,  it  is  easily  administered,  either  in 
powder  or  suspended  in  a  neutral  syrup,  to  children.  An  acid 
with  the  drug  or  immediately  following  develops  a  bitter  taste. 
The  objections  to  the  preparation  are  its  expense  and  the  fact 
that  it  is  patented. 

The  tannate  of  quinine,  on  account  of  its  small  proportion  of 


TREATMENT  357 

alkaloid  and  slight  solubility,  has  been  until  recently  only  rarely 
employed  in  the  therapy  of  malaria.  The  Italian  Government, 
in  an  effort  to  supply  a  tasteless  salt  of  quinine  for  children, 
has  been  dispensing  tannate  of  quinine  in  the  form  of  choco- 
late confections.  A  commission  of  members  of  the  Superior 
Council  of  Health,  appointed  to  investigate  the  results  obtained 
by  this  method  of  administration,  reported  adversely.  They 
concluded  that  the  tannate  of  quinine  is  one  of  the  most  insol- 
uble preparations  of  quinine,  and  that  it  is  weakly  and  slowly 
acted  upon  by  the  digestive  fluids;  that  the  fat  of  the  cocoa 
retards  the  action  of  the  digestive  fluids  upon  the  quinine  and 
causes  it  to  deteriorate  under  the  influence  of  the  air.  This 
report  was  the  occasion  of  a  unanimous  remonstrance  by 
numerous  physicians  who  obtained  excellent  results  from  the 
use  of  the  tannate. 

The  experience  of  the  writer  with  this  salt,  together  with 
the  reports  of  the  Italian  physicians,  leads  to  the  following 
conclusions : 

1.  The  tannate  of  quinine  is  almost  completely  absorbed 
from  the  alimentary  tract. 

2.  It  is  more  slowly  absorbed  and  more  slowly  eliminated 
than  the  other  salts  of  quinine,  and  remains  in  the  system 
longer. 

3.  A  small  quantity  only  of  the  salt  is  acted  upon  by  the  gas- 
tric juice,  but  is  largely  absorbed  from  the  bowel  after  contact 
with  the  bile  and  pancreatic  juice. 

4.  It  is  not  absorbed  when  injected  into  the  rectum. 

5.  It  is  better  tolerated  by  the  stomach,  intestines,  and  ner- 
vous system  than  the  sulphate. 

6.  The  clinical  results  with  the  tannate  of  quinine  are  en- 
tirely satisfactory. 

7.  Being  nearly  tasteless,  it  is  especially  adapted  to  the  treat- 
ment of  malaria  in  children. 

8.  It  has  a  good  effect  upon  diarrhea  and  dysentery  compli- 
cating malaria. 

9.  It  is  several  times  less  expensive  than  any  other  tasteless 
preparation  of  quinine. 

Methods  of  Administration  of  Quinine. — Administration 


358  THE    STUDY   OF   MALARIA 

by  the  Mouth. — In  simple  cases  of  malaria,  administration  of 
quinine  by  the  mouth  is  the  rule ;  by  other  methods  the  excep- 
tion. It  is  probable  that  ninety-nine-one-hundredths  of  the 
quinine  consumed  is  given  by  the  oral  route. 

There  are  those,  not  objecting  to  the  taste  of  quinine,  who 
will  take  it  in  the  powdered  form;  in  fact,  it  is  a  common 
method  among  the  Southern  negroes  to  lick  it  from  the  palm 
of  the  hand.  The  taste  is,  however,  so  repulsive  to  most  per- 
sons that,  with  the  exception  of  the  tannate  and  euquinine,  it 
must  be  given  in  some  other  form. 

The  same  objection  applies  to  giving  the  drug  in  solution, 
though  this  is  unquestionably  the  most  reliable  form  in  which 
to  give  it  by  the  mouth,  but  for  obvious  reasons  it  cannot  be 
so  extensively  employed  in  this  manner  in  private  practice. 
The  solution  is  more  quickly  and  completely  absorbed.  The 
bimuriate  and  the  bisulphate  are  the  salts  most  suitable  for 
solution,  but  if  neither  of  these  is  at  hand  the  sulphate  may  be 
employed  by  adding  a  drop  of  dilute  hydrochloric  or  sulphuric 
acid  for  each  grain  of  the  quinine. 

The  most  efficient  vehicle  for  disguising  the  taste  of  the 
sulphate  of  quinine  is  the  syrup  of  yerba  santa.  Two  grains 
of  quinine  to  the  dram  of  the  syrup  is  the  suitable  proportion. 
Syrup  of  chocolate,  fluidextract  of  licorice,  ginger,  coffee, 
milk,  honey,  olive  oil,  and  other  media  have  been  recommended, 
but  are  far  from  satisfactory.  Acid  fruit  juices  and  syrups 
usually  enhance  the  bitter  taste. 

Where  prejudice  against  quinine  makes  it  necessary  to  dis- 
guise the  appearance  of  the  drug,  this  may  be  accomplished 
effectively  by  adding  a  small  quantity  of  charcoal,  turmeric, 
or  methylene-blue  to  the  bimuriate,  bisulphate,  or  other  salt. 

Pills  and  tablets  are  convenient  to  administer  and  not  un- 
pleasant to  take,  but  cannot  be  relied  upon.  The  coating  often 
becomes  so  hard  as  to  make  solution  difficult  or  impossible. 
The  writer  has  several  times  seen  quinine  given  in  this  form 
pass  from  the  bowel  wholly  unaffected.  Pills  and  tablets 
should  not  be  given  when  capsules  can  be  obtained.  Capsules, 
when  fresh,  are  easily  dissolved.  If  there  is  any  doubt  as 
to  their  quality  they  may  be  punctured  several  times  in  each 


TREATMENT  359 

end  with  a  pin,  or  may  be  followed  by  a  few  drops  of  a  dilute 
mineral  acid. 

In  the  absence  of  capsules  quinine  has  been  rolled  in  a  little 
ball  with  cigarette  paper.  Absorption  is  extremely  slow  and 
uncertain,  and  this  method  should  not  be  resorted  to. 

The  tannate  of  quinine  has  been  compounded  with  the  choco- 
late confection  for  administration  to  children,  and  in  this  form, 
if  reliably  made,  is  readily  taken,  and  in  sufficient  dose  is 
efficient. 

Hypodermic  Method. — Quinine  was  used  hypodermically  at 
least  as  early  as  1863,  when  Bourdon289  employed  the  sulphate 
dissolved  in  water  with  tartaric  acid.  The  same  year  Moore411 
recommended  the  use  of  30  grains  of  the  sulphate  of  quinine 
dissolved  in  y2  ounce  of  water  by  means  of  8  or  10  drops 
of  dilute  sulphuric  acid,  from  1  to  1^  drams  of  this  solu- 
tion to  be  used  at  a  dose.  Bad  results  were  common. 
Arnould,412  in  1867,  reported  in  95  cases  thus  injected  2 
indurated  nodes,  4  eschars,  and  15  abscesses.  In  1888  Beur- 
mann  and  Villejean412  introduced  for  hypodermic  use  the  bi- 
muriate  in  the  following  formula,  which  is  still  widely  em- 
ployed : 

Quinine  bimuriate   5  gm. ; 

Distilled  water  to    10  cc. 

Kobner86   recommends : 

Quinine  hydrochlorate   5-1  gm. ; 

Glycerine,  1 

Distilled  water  J aa    2  gm- 

Grimmaux  :86 

Quinine  hydrochlorico-sulphate 5  gm. ; 

Aqua  dest 6  cc. 

Klein  :96 

Quinine  hydrobromate   2  gm. ; 

Sulphuric    ether    12  cc. ; 

Alcohol    q.   s.  20  cc. 

Triulzi86  added  antipyrine  to  promote  solution  and  diminish 
pain: 

Quinine  muriate  3  gm. ; 

Antipyrine    2  gm. ; 

Aqua 6  cc. 


360  THE    STUDY   OF  MALARIA 

Vincent  and  Burot:96 

Quinine  muriate  3  gm. 

Analgesin    2  gm. 

Aqua    6  cc. 


.86 


Gaglio : 

Quinine  hydrochlorate  3  gm. ; 

Urethane 3  gm. ; 

Aqua 5  cc. 

The  addition  of  cocaine  has  been  recommended  also  to  lessen 
the  pain. 

The  most  suitable  salt  of  quinine  for  injection  is  unques- 
tionably the  bimuriate.  The  tablets  of  bimuriate  of  quinine 
and  urea  are  convenient  and  insure  accurate  dosage.  The  3- 
grain  tablets  contain  approximately  2^2  grains  of  the  quinine 
salt. 

The  advantages  of  giving  quinine  by  the  needle  in  pernicious 
malaria  are  obviously  being  able  to  administer  it  to  patients 
unable  to  swallow  or  to  retain  it,  and  the  certainty  and  prompt- 
ness of  absorption.  Nevertheless,  these  great  benefits  are  some- 
what discounted  by  the  bad  results  which  sometimes  appear. 
Formerly  tetanus  was  to  be  feared.  Bartholow413  mentions 
several  such  cases  reported  from  New  Orleans  and  2  occurring 
in  one  regiment  of  the  British  Indian  Army.  Vincent,414  in  a 
late  report,  recalls  the  numerous  cases  following  the  sub- 
cutaneous use  of  quinine.  McCampbell415  speaks  of  a  fatal 
case  of  tetanus  shortly  following  a  hypodermic  injection  of 
the  hydrochlorate  of  quinine,  though  the  experiments  of  this 
writer  fail  to  corroborate  those  of  Vincent  to  the  effect  that 
the  injection  of  quinine  favors  the  development  of  the  tetanus 
bacillus.  In  the  late  French  campaign  in  Madagascar  6  cases 
of  tetanus  subsequent  to  hypodermics  of  quinine  came  under 
observation.  But  there  are  other  consequences  which,  while 
not  so  deadly,  are  more  commonly  met.  Nodules,  necrosis, 
sloughing-,  and  abscess  formation  are  referred  to.  Plehn171 
and  Blumchen416  have  frequently  seen  necroses  and  abscesses 
result  from  hypodermics  of  quinine.  Thayer98  says  there  is 
always  danger  of  subsequent  abscess  or  necrosis.  Laveran1 
states  that  injections  made  into  the  skin  often  give  rise  to 


TREATMENT  36 1 

eschars.  Manson417  has  often  seen  induration,  if  not  abscess, 
follow  the  hypodermic  injection  of  quinine  conducted  in  the 
ordinary  way.  Bonnette,412  Mauviez412  and  LeDantec226  say 
that,  in  spite  of  the  greatest  aseptic  precautions,  eschars  and 
abscesses  will  sometimes  result.  Craig418  has  observed  ab- 
scesses in  about  20  per  cent,  of  the  cases,  and  often  had  nodular 
elevations  at  the  seat  of  puncture  which  persisted  for  some  time. 
Gros,419  Shoemaker,420  and  Tyson421  have  abandoned  the 
method  on  account  of  the  frequency  of  inflammation  and  ab- 
scess formation. 

These  results,  however,  should  not  prevent  the  use  of  quinine 
injections  in  the  treatment  of  pernicious  malaria,  as  such 
effects  are,  in  a  great  measure,  preventable.  To  this  end  there 
are  three  measures  of  importance :  First,  asepsis ;  second,  di- 
lute solutions,  and,  third,  deep  injections. 

The  first  is  at  the  present  day  probably  the  least  often 
neglected,  as  most  physicians  realize  the  importance  of  steriliza- 
tion, and  a  spoonful  of  water  and  a  few  matches  are  sufficient 
to  effect  it  on  the  part  of  the  solution  and  needle,  and  soap 
and  water  are  almost  omnipresent. 

The  necessity  of  employing  a  dilute  solution  has  been  all 
but  ignored.  Nearly  all  writers  on  the  subject  lay  great  stress 
on  the  need  of  asepsis,  but  with  few  exceptions  even  mention 
the  evils  of  too  concentrated  solutions.  Strong  solutions  of 
quinine  injected  into  the  tissues  cause  a  wall  of  necrosis  around 
the  solution,  preventing  absorption  and  paralyzing  phago- 
cytosis, resulting,  even  if  the  solution  is  sterile,  in  nodes  or 
ugly  chemic  sloughs.  It  is  in  all  probability  this  chemic  irrita- 
tion of  the  cells  which  allows  of  bacterial  infection  following 
the  injections  of  solutions  not  properly  sterilized,  and,  no 
matter  how  sterile  the  solution,  if  too  concentrated,  a  nodule 
or  chemic  slough  is  apt  to  result.  Witness  the  frequency  with 
which  unsterilized  solutions  of  morphine  and  other  drugs  are 
given  without  the  slightest  bad  consequence. 

For  injection  purposes  the  following  formula  is  most  suit- 
able: 

Quinine  bimuriate  1  gm.  (gr.  xv)  ; 

Water    10  cc.     (dr.  iiss) . 


362  THE    STUDY    OF    MALARIA 

As  much  of  this  as  needed  may  be  injected  in  one  or  several 
locations. 

The  solutions  should  not  be  injected  hypodermically,  but 
intramuscularly,  since  in  the  latter  location  the  injection  is 
more  certainly  absorbed,  is  less  apt  to  cause  induration  and 
abscess,  and  is  less  painful.  In  some  cases  of  pernicious 
malaria  the  superficial  circulation  is  very  poor,  absorption  cor- 
respondingly inadequate,  and  necrosis  almost  inevitable  if  the 
quinine  is  not  deeply  injected.  In  a  case  of  algid  malaria  in 
my  practice  where  the  quinine  was  given  hypodermically  the 
site  of  injection  began  to  turn  blue  within  ten  minutes  and 
was  almost  black  within  two  hours. 

The  initial  dose  should  ordinarily  be  15  grains.  Afterward 
from  5  to  10  grains  should  be  injected  every  six  or  eight  hours 
as  long  as  the  symptoms  demand  it.  For  children  under 
five  years  the  first  dose  may  be  1^  grains  for  each  year  of 
age.  The  statement  of  Homem,157  that  in  the  administration 
of  quinine  in  pernicious  malaria  it  is  best  rather  to  sin  by  prod- 
igality than  by  parsimony,  is  open  to  question.  While  there 
are  few  drugs  so  potent  as  quinine  having  so  few  toxic  effects, 
bad  results  do  sometimes  follow  excessive  doses.  Schellong92 
noticed  that  large  doses  added  to  the  insult  to  the  nervous 
system  and  had  a  depressing  effect  on  the  heart.  As  Plehn5 
expresses  it,  there  is  a  universal  tendency  to  attribute  all  bad 
phenomena  to  the  disease  and  all  favorable  ones  to  the  remedy. 
However,  after  using  in  5  cases  5  to  6  grams  in  divided  doses, 
repeated  at  short  intervals  during  the  height  of  fever,  this 
accurate  observer  noted  considerable  depression  of  the  heart, 
nervous  system,  and  general  condition  of  the  patients. 

Most  of  the  continental  writers  recommend  the  Pravaz  or 
Luer  syringes,  with  platin-iridium  needles,  but  the  ordinary 
antitoxin  syringe,  as  used  by  Sutherland168  for  this  purpose, 
answers  as  well.  A  soft-rubber  tubing  connection  between  the 
needle  and  the  nipple  of  the  syringe  is  advantageous,  as  it  may 
prevent  the  breaking  of  a  needle  in  a  struggling  patient.  One 
of  these  syringes,  a  small  sterilizing  pan,  and  alcohol  lamp  do 
not  occupy  much  space,  and,  being  almost  indispensable  in  these 
cases,  should  be  easily  accessible  during  the  malarial  season  to 


TREATMENT  363 

the  physician  in  a  malarial  locality,  who  often  sees  these  cases 
miles  from  his  office,  when  time  is  a  matter  of  life  and  death. 
The  ordinary  hypodermic  syringe  may  be  used  in  an  emer- 
gency, but  to  use  a  sufficient  quantity  of  a  properly  diluted 
solution  a  number  of  injections  have  to  be  made. 

The  best  location  for  injection  is  in  the  gluteal  region  well 
above  the  ischial  tuberosities,  though  the  interscapular  region 
is  often  chosen. 

The  technic  of  intramuscular  injections  of  quinine  may  be 
summarized  in  these  precautions:  Have  the  solution  freshly 
made,  thorough,  dilute,  and  sterile;  render  the  syringe  and 
the  injection  site  aseptic ;  insert  the  needle  into  muscular  tissue, 
and  avoid  breaking  the  needle. 

Intravenous  Method. — In  1890  Bacelli422  introduced  the  in- 
travenous administration  of  quinine  in  the  treatment  of  perni- 
cious malaria,  claiming  thereby  to  have  reduced  the  mortality 
from  17  to  6  per  cent.     The  following  formula  was  used: 

Quinine  hydrochlorate i.oo  gm. ; 

Sodium  chloride    75  gm. ; 

Distilled  water    10.00  cc. 

The  arm  is  bound  above  the  elbow  in  order  to  distend  the 
veins  of  the  forearm,  into  one  of  which  the  needle  is  intro- 
duced in  the  direction  of  the  blood  current,  and  the  solution 
injected  very  slowly  after  removing  the  constriction.  The 
puncture  should  be  covered  with  a  sterile  dressing.  The  solu- 
tion should  be  warm  and  sterile,  and  care  should  be  taken 
that  no  air  is  injected.  If  swelling  occurs  at  site  of  the  injec- 
tion it  is  evident  that  the  vein  has  not  been  entered.  It  is  said 
that  1  gram  of  quinine  thus  injected  produces  a  solution  in  the 
blood  of  1  :  5,000,  which  is  the  strength  deemed  necessary  by 
Binz  to  destroy  protozoa.  Rogers44  thinks  well  of  this  method, 
and  has  abandoned  in  favor  of  it  the  subcutaneous  route.  How- 
ever, it  probably  has  no  advantages  over  the  intramuscular 
administration.  Moreover,  it  is  not  infrequently  almost  impos- 
sible to  locate  the  veins,  especially  in  young  negroes. 

Hypodermoclysis. — Quinine  dissolved  in  normal  salt  solution 
given  by  hypodermoclysis  has  been  recommended  by  Grail256 


364  THE    STUDY   OF   MALARIA 

and  others.  From  10  to  30  grains  of  the  bimuriate  are  dis- 
solved in  a  pint  of  normal  salt  solution,  and  as  much  as  desired 
is  injected  into  the  loose  subcutaneous  tissue.  It  is  extolled 
especially  by  Glatard86  in  the  treatment  of  children  suffering 
with  pernicious  malaria.  This  method  is  probably  not  adapted 
to  the  treatment  of  algid  malaria  on  account  of  the  deficient 
superficial  circulation.  Besides,  the  necessary  apparatus  is  fre- 
quently wanting. 

Gutierrez423  had  success  with  injections  of  quinine  directly 
into  the  spleen,  but  such  a  dangerous  procedure  is  entirely 
unjustifiable.  Fleury,424  acting  upon  the  theory  that  the  nearer 
the  spleen  the  quinine  is  injected  the  better  the  result,  injected 
deeply  into  the  structures  below  the  ribs  in  the  midaxillary  line 
upon  the  left  side.  His  results  do  not  appear  to  have  excelled 
those  following  injections  in  other  sites. 

Jousset159  treated  pernicious  malaria  with  injections  of 
quinine  into  the  trachea  by  inserting  the  needle  immediately 
below  the  cricoid  cartilage  and  injecting  a  10  per  cent,  solution 
drop  by  drop. 

Le  Dantec226  suggests  that  in  cases  of  tetanic  pernicious 
malaria  the  subarachnoid  injections  of  quinine,  after  the 
method  of  Jaboulay,  might  prove  efficacious.  So  far  as  known, 
this  method  has  not  been  tried  in  this  condition. 

Rectal  Administration. — This  method,  though  uncertain,  is 
of  value  where  quinine  cannot  be  retained  by  the  stomach,  and 
there  are  objections  to  the  intramuscular  injection,  especially 
in  children.  It  may  also  be  used  as  an  adjuvant  to  the  intra- 
muscular or  intravenous  injection  in  pernicious  cases.  A 
soluble  salt  should  be  used,  preferably  the  bimuriate.  The 
water  should  be  about  the  temperature  of  the  body,  and  should 
not  exceed  a  few  ounces  in  quantity.  Two  or  three  times  as 
much  quinine  should  be  given  by  the  rectum  as  by  the  mouth, 
and  the  injection  should  be  made  high  into  the  bowel.  Ten 
or  15  drops  of  tincture  of  opium  should  be  added  to  prevent 
tenesmus  and  aid  retention.  Antipyrine  has  been  recommended 
by  some,  but  should  be  used  with  care  where  there  is  depres- 
sion. A  cleansing  injection  should  be  given  first  if  the  patient 
is  conscious. 


TREATMENT  365 

The  writer  has  had  no  experience  with  quinine  given  in 
rectal  suppositories,  but  these  are  highly  recommended  by  Shoe- 
maker.420 Five  or  10  grains  should  be  contained  in  each  sup- 
pository, in  which  may  also  be  included  a  small  quantity  of  the 
extract  of  belladonna  to  facilitate  retention. 

Epidermic  Administration. — The  use  of  quinine  mixed  with 
fats  and  oils  and  rubbed  into  the  skin  is  not  to  be  relied  upon, 
since  little,  if  any,  quinine  is  absorbed  by  the  skin. 

Time  of  Administration  and  Dose. — With  reference  to  the 
time  when  the  drug  is  given,  there  are  three  chief  modes  of 
giving  quinine : 

(1)  The  method  of  Torti,  a  single  dose  before  the  parox- 
ysm; (2)  the  method  of  Sydenham,  a  single  dose  in  the  decline 
of  the  paroxysm,  and  (3)  the  method  of  fractional  doses. 

The  first  two  methods  are  adapted  only  to  the  benign  infec- 
tions. 

The  efficacy  of  the  method  of  Torti  rests  upon  the  fact  that 
the  parasites  are  most  susceptible  to  the  action  of  quinine  imme- 
diately after  sporulation,  while  free,  before  having  entered  the 
red  cells.  It  presupposes  an  accurate  knowledge  of  the  hour 
at  which  the  next  paroxysm  will  occur,  based  obviously  upon  a 
definite  history  of  repeated  paroxysms,  a  temperature  chart, 
or  blood  examinations  sufficiently  accurate  to  determine  not 
only  the  type  of  the  organism,  but  its  exact  stage.  It  is  evident 
that  in  private  practice,  in  the  patient  seen  in  the  first  access, 
the  prediction  of  the  next  paroxysm  must  usually  depend  upon 
the  results  of  the  examination  of  the  blood,  and  that  this  must 
be  repeated  if  the  stage  is  not  recognized  at  the  first  examina- 
tion. Unless  this  can  be  done  quinine  should  not  be  admin- 
istered in  this  way,  for,  even  if  the  type  of  malaria  present  is 
known,  there  are  two  conditions  which  may  render  the  single 
dose  futile :  first,  anticipation  of  the  paroxysm ;  second,  a 
multiple  infection.  Even  where  the  blood  is  carefully  ex- 
amined, it  may  happen,  in  double  infections,  that  only  one 
group  can  be  detected  in  the  peripheral  blood. 

By  this  method,  also  known  as  the  Roman  method,  the 
quinine  is  given  in  a  single  dose  of  about  15  grains  from  four 
to   six   hours   before   the   next   succeeding   paroxysm.      This 


366  THE  STUDY   OF    MALARIA 

paroxysm  is  not  prevented ;  in  fact,  it  may  be  entirely  unmodi- 
fied; but  such  a  dose,  properly  timed,  usually  secures  apyrexia 
subsequently  for  several  days. 

In  double  tertian  infections  a  single  dose  given  in  this  way 
may  change  the  quotidian  paroxysms  into  tertian,  and  if  re- 
peated, in  multiple  tertian  and  quartan  infections,  constitutes 
a  sort  of  fractional  sterilization  of  the  blood. 

The  method  of  Sydenham,  the  English  method,  consists  of 
a  single  dose,  averaging  15  grains,  given  in  the  sweating  stage 
or  the  decline  of  the  paroxysm.  This  dose  usually  prevents 
succeeding  paroxysms;  if  one  should  occur  it  is  usually  abor- 
tive. 

This  method  requires  less  knowledge  of  the  exact  nature  of 
the  infection  and  of  the  stage  of  development  than  the  former 
method,  hence  it  may  be  more  effectively  applied  by  the  busy 
practitioner.  What  experience  the  writer  has  had  with  it  has 
been  satisfactory. 

The  third  method,  that  of  small  doses  at  frequent  intervals, 
has  numerous  advantages  over  the  one-dose  methods. 

1.  Quinine  given  in  this  way  is  better  borne  by  the  digestive 
and  nervous  systems. 

2.  The  loss  of  one  dose  by  vomiting  or  failure  of  absorption 
is  not  of  so  much  importance. 

3.  The  method  is  adapted  to  tertian,  quartan,  or  estivo- 
autumnal  infections;  this  is  important,  for  sometimes  these 
cannot  be  differentiated  clinically. 

4.  It  is  adapted  especially  to  estivo-autumnal  infections 
where  sporulation  is  not  so  nearly  synchronous. 

5.  The  time  of  administration  is  not  dependent  on  parasitic 
findings  or  definite  stages,  both  of  which  may  be  obscure  where 
the  patient  has  previously  taken  quinine. 

6.  An  experience  in  many  hundreds  of  cases  has  proved  its 
value. 

The  writer  gives  quinine  in  this  way  almost  exclusively. 
The  average  dose  is  a  grain  an  hour,  given  usually  2  grains 
every  two  hours,  3  grains  every  three  hours,  or  4  grains  every 
four  hours  day  and  night.  It  is  especially  important  that  the 
drug  be  given   during  the   night,   since  thus   only   may  the 


TREATMENT  367 

blood  be  charged  during  the  day,  when  speculation  usually 
occurs. 

It  is  not  necessary  to  defer  or  discontinue  the  use  of  quinine 
on  account  of  fever,  as  is  believed  by  some.  More  than  four- 
score years  ago  Maillot  showed  that  to  withhold  the  drug  for 
this  reason  was  not  only  useless,  but  dangerous. 

Cinchonism  is  no  guide  to  the  quantity  to  be  given ;  it  is  not 
the  patient  toward  which  the  quinine  is  directed,  but  the  para- 
sites. 

The  specific  should  not  be  discontinued  as  soon  as  the  tem- 
perature is  normal,  but  should  be  kept  up  for  at  least  two 
days  longer  in  the  quantity  employed  during  the  fever.  There- 
after about  15  grains  on  two  successive  days  of  each  week 
should  be  given  for  at  least  two  or  three  months  to  prevent 
relapse,  even  though  the  patient  leave  the  malarial  locality. 
A  few  days'  treatment  with  quinine  no  more  cures  malaria 
than  does  a  few  weeks'  rubbing  with  mercury  cure  syphilis. 

Hygienic  and  Symptomatic  Treatment. — Rest  is  impor- 
tant in  the  treatment  of  malaria  not  only  during  the  stage  of 
active  symptoms,  but  during  convalescence.  Exercise  may 
counteract  the  benefits  of  quinine;  it  is  not  uncommon  to  see 
cases  yield  after  confinement  to  bed  which  had  previously  re- 
sisted quinine.  A  relapse  may  be  provoked  by  a  too-early 
resumption  of  duty.  Rest  is  especially  important  in  the  treat- 
ment of  estivo-autumnal  infections. 

Buttermilk  is  one  of  the  most  acceptable  and  easily  retained 
articles  of  diet.  Sweet  milk,  meat  broths,  vegetable  soups, 
fruit  juices  with  egg  albumen,  soft-boiled  eggs,  and  toast  are 
usually  allowable.  Where  there  is  much  gastric  disturbance 
food  had  better  be  withheld  temporarily. 

The  room  and  bed  should  be  screened;  in  this  way  only 
can  other  members  of  the  household  be  satisfactorily  protected. 
The  room  should  be  thoroughly  ventilated  and  the  patient 
protected  from  draughts. 

It  is  customary  to  begin  the  medical  treatment  with  a  purge. 
Calomel  is  the  drug  most  easily  administered  and  retained. 
The  drug  need  not  exceed  5  or  6  grains,  and  should  be  followed 
by  a  saline.     The  quinine  should  not  be  delayed  for  the  action 


368  THE    STUDY   OF    MALARIA 

of  the  purgative.  As  has  been  said,  "cases  originally  violent 
almost  invariably  die  while  preparing  for  the  quinine,  and  those 
of  moderate  severity  become  worse  under  the  preparation."™ 
Calomel  has  been  frightfully  abused  in  most  malarial  coun- 
tries. It  was  formerly  the  universal  practice  to  give  the  drug 
until  the  gums  were  "touched"  and  the  teeth  irreparably  dam- 
aged. It  was  more  the  abuse  of  calomel  than  of  any  other 
drug  that  led  Oliver  Wendell  Holmes425  to  declare  that,  ex- 
cepting a  few  drugs,  "if  the  whole  materia  medica,  as  now 
used,  could  be  sunk  to  the  bottom  of  the  sea  it  would  be  all 
the  better  for  mankind — and  all  the  worse  for  the  fishes." 

During  the  cold  stage  blankets,  hot  drinks,  and  the  external 
application  of  heat  are  indicated.  Atropine  hypodermically  is 
useful,  and  morphine  is  indicated  in  some  cases. 

In  the  hot  stage,  if  the  temperature  runs  high,  cold  applica- 
tions to  the  head,  tepid  sponging,  and  cold  rectal  injections 
may  be  used.  The  coal-tar  antipyretics  are  not  often  indicated. 
Cold  drinks  may  be  given. 

For  the  headache  cold  applications,  codeine,  and  acetanilid, 
or  chloral  and  bromide  of  soda  are  useful,  and,  if  the  pain 
demands  it,  morphine  need  not  be  withheld.  If  nervousness 
is  marked  the  monobromated  camphor  should  be  administered 
with  the  quinine  in  capsules,  or  the  bromide  of  soda,  in  solu- 
tion, with  each  dose  of  the  specific. 

For  vomiting,  if  intense  and  not  relieved  by  the  application 
of  a  mustard  plaster  to  the  epigastrium,  morphine  should  be 
employed  subcutaneously. 

Chronic  Malaria. — In  the  treatment  of  chronic  malaria  two 
parasitic  cycles  have  to  be  combated,  the  schizogonic  and  the 
parthenogenetic.  The  treatment  of  the  asexual  cycle  of  para- 
sitic evolution  in  chronic  malaria  is  that  of  acute  malaria. 

The  tendency  to  relapse  at  multiples  of  approximately  seven 
days  has  long  been  recognized,  these  periods  being  known  as 
the  septenary  periods.  It  is  now  known  that  these  relapses 
depend  upon  the  sporulation  of.  the  parthenogametes,  a  cycle 
difficult  to  interrupt  except  during  the  stage  of  free  spores. 

After  successively  meeting  the  active  symptoms  by  quinine, 
administered  as  above  outlined,  the  prevention  of  a  relapse  is 


TREATMENT  369 

to  be  accomplished  by  giving  15  grains  of  quinine  every  sixth 
and  seventh  days  for  a  period  of  not  less  than  three  months. 
The  administration  of  a  valuable  salt  of  quinine  in  this  manner 
has  rarely  failed,  in  the  writer's  experience,  to  cure  the  most 
obstinate  case  of  chronic  malaria.  The  quinine  is  usually  given 
in  3-grain  doses  every  three  hours  until  five  are  taken. 

The  hygienic  treatment  is  even  of  greater  importance  in 
the  management  of  chronic  malaria  than  in  acute.  Many 
secondary  factors  may  arouse  latent  malaria,  and  these,  which 
have  been  mentioned  in  the  section  on  Etiology,  should  be 
assiduously  avoided. 

Cachexia. — Nothing  is  more  discouraging  to  the  physician 
than  the  treatment  of  cachetics  in  whom  the  poor  hygienic  con- 
ditions cannot  be  corrected,  which  is  not  rarely  the  case.  The 
two  chief  principles  involved  in  the  treatment  of  cachexia  are, 
first,  the  prevention  of  active  outbreaks  of  malaria,  and,  sec- 
ond, the  improvement  of  the  general  condition  of  the  patient 
by  appropriate  hygiene. 

Quinine  is  most  effectively  given  upon  two  successive  days 
in  each  week,  as  described.  This  alone,  however,  will  rarely 
effect  a  cure  except  in  the  mildest  cases. 

Where  it  is  practicable  a  complete  change  of  climate  should 
be  advised.  Without  this  very  little  can  be  accomplished  for 
cases  of  severe  degree.  A  wholesome,  nutritious,  and  digest- 
ible diet  should  be  prescribed.  The  digestion  is  often  impaired 
and  stomachic  tonics  may  be  indicated.  Exposure  to  inclement 
weather  must  be  avoided  on  account  of  the  dangers  of  pneu- 
monia. Occupations  which  subject  the  cachectic  to  violent 
exertion  or  to  bodily  harm  should  be  interdicted  for  fear  of 
rupture  of  the  spleen.  Regular  hours  must  be  kept  and  con- 
stipation overcome. 

Of  drugs  other  than  quinine,  arsenic  has  the  best  reputation. 
It  should  be  given  in  rather  large  doses  of  the  arsenous  acid 
or  Fowler's  or  Donovan's  solutions.  Atoxyl  has  recently  been 
introduced  into  the  treatment  of  malarial  cachexia.  It  is 
employed  hypodermically,  one-third  grain  being  a  moderate 
dose.  The  writer's  limited  experience  with  this  method  has 
been    rather    favorable   than   otherwise.      The   possibility    of 

24 


37©  THE    STUDY  OF    MALARIA 

amaurosis  as  a  toxic  result  of  atoxyl  should  be  borne  in 
mind. 

Iron  is  nearly  always  indicated ;  the  organic  preparations  of 
iron  and  manganese  are  usually  well  borne  by  the  stomach. 
The  pill  of  Blaud's  mass,  2J/2  grains;  atoxyl,  one-third  grain, 
may  be  tried,  or  the  classic  antimalarial  pill  of  iron,  quinine, 
arsenic,  and  strychnine. 

Injections  of  medicaments  directly  into  the  spleen,  as  some- 
times advised,  are  unjustifiable. 

Counter-irritation  over  the  splenic  area  may  aid  in  the  re- 
duction of  the  enlarged  spleen.  The  best  agent  is  the  ointment 
of  the  red  iodide  of  mercury.  A  piece  the  size  of  a  pea  or 
larger  should  be  thoroughly  rubbed  in,  the  splenic  region  being 
bared  to  the  sun's  rays  or  to  the  heat  of  a  fire.  This  should 
be  repeated  daily  until  the  skin  becomes  so  irritated  as  to 
make  friction  painful,  when  it  should  be  discontinued,  to  be 
resumed  again  when  the  condition  of  the  skin  will  permit. 
Iodine,  turpentine,  mustard,  firing  with  the  actual  cautery, 
and  other  counter-irritants  have  been  recommended. 

Hydrotherapeutics  and  electricity  have  not  given  general 
satisfaction.  Their  use  is  sometimes  followed  by  an  active 
outburst  of  malaria. 

While  the  .r-rays  have  a  destructive  effect  upon  certain 
protozoa,  they  do  not  appear  to  have  such  action  upon  the 
parasites  of  malaria  within  the  circulation.  Demarchi,426  as 
a  result  of  his  experiments,  is  convinced  that,  while  these  rays 
are  useless  against  the  infection  itself,  they  appear  to  have 
a  beneficial  effect  upon  the  enlarged  spleen  when  the  parasites 
have  disappeared  spontaneously  or  as  the  result  of  medication. 

Splenectomy  may  be  performed  in  very  anemic  patients  with 
large,  painful  spleens,  especially  if  freely  movable,  in  whom  a 
change  of  climate  is  impossible  and  therapeutic  measures  have 
failed.  The  writer  had  the  opportunity  of  treating  an  obsti- 
nate case  of  estivo-autumnal  malaria  in  an  adult  female  who 
had  had,  several  years  previously,  the  spleen  removed  on  ac- 
count of  malarial  cachexia.  Hemoglobin  percentage  was  only 
slightly  affected  by  the  attack,  and  convalescence  was  rapid. 

Brachio427  has  recently  suggested  a  unique  method  of  treat- 


TREATMENT  37 1 

ment  of  splenomegaly.  He  had  observed  that  in  patients  with 
splenic  enlargements  who  suffered  suppurative  complications, 
as  mastoiditis,  empyema,  cancrum  oris,  etc.,  the  spleen  rapidly 
diminished  in  size.  At  the  same  time  a  leukocytosis  was  pro- 
duced where  these  cells  had  previously  been  diminished,  and 
to  this  phenomenon  he  attributed  the  improvement.  In  order 
to  produce  leukocytosis  this  writer  injected  subcutaneously 
5  minims  of  turpentine  in  the  splenic  region,  which  resulted 
in  abscess  formation  and  a  consequent  increase  in  the  number 
of  leukocytes.  Nearly  20  cases  were  treated  in  this  manner 
with  the  most  encouraging  results.  While  in  cases  with  very 
large  spleens  it  was  necessary  to  repeat  the  injection,  in  only 
I  case  was  the  third  injection  required. 

Treatment  of  Malaria  in  Children. — In  the  treatment  of 
malaria  in  children  it  is  the  practice  of  the  writer  to  administer 
the  quinine  at  short  intervals  every  two  or  three  hours. 

While  children  bear  quinine  in  relatively  larger  doses  than 
adults,  the  size  of  the  dose  should  be  regulated  by  the  severity 
of  the  attack  and  the  age  of  the  patient.  In  average  cases 
children  from  one-half  to  two  years  of  age  may  be  given 
from  ^  to  1  grain  of  quinine  every  three  hours,  from  three 
to  five  years  from  1  to  2  grains,  and  from  six  to  ten  years 
from  2  to  23/2  grains.  These  quantities  may  be  increased  in 
severe  attacks. 

The  drug  is  ordinarily  given  by  the  mouth.  Where  capsules 
cannot  be  used,  recourse  must  be  had  to  a  tasteless  preparation 
or  to  a  disguising  vehicle.  Euquinine  and  the  tannate  of 
quinine  are  the  best  of  the  tasteless  preparations.  The  former 
must  be  given  in  slightly  larger  doses,  the  latter  up  to  double 
the  doses  indicated  above.  The  most  efficient  liquid  for  dis- 
guising the  taste  of  the  sulphate  of  quinine  is  the  syrup  of 
yerba  santa,  at  least  1  dram  of  which  should  be  given  for 
each  2  grains  of  the  quinine.  In  cases  with  pernicious  symp- 
toms the  drug  should,  of  course,  be  injected  intramuscularly. 
Rectal  administration  of  a  solution  or  suppository  may  be 
employed  to  supplement  other  modes.  The  buttocks  should 
be  pressed  together  for  half  an  hour  after  insertion  to  aid 
retention. 


372  THE    STUDY    OF    MALARIA 

Calomel,  mercury  with  chalk,  and  castor  oil  are  efficient 
purgatives  in  the  treatment  of  malaria  in  children. 

Treatment  of  Complications. — When  malaria  is  compli- 
cated with  other  diseases  each  should  receive  appropriate  treat- 
ment. The  malaria  should  be  promptly  treated  as  under  ordi- 
nary circumstances.  Only  a  few  complications  need  special 
consideration. 

For  rupture  of  the  spleen  immediate  laparotomy  should  be 
performed.  With  early  operation  over  half  recover,  without 
operation  the  mortality  is  nearly  ioo  per  cent. 

Abscess  of  the  spleen  is  a  surgical  condition.  The  choice 
of  operation  between  splenectomy  and  splenotomy  must  be 
based  upon  individual  conditions.  Two  cases  reported  by 
Bell428  and  by  Goltman429  recovered  after  operation. 

In  the  treatment  of  quinine  amaurosis  the  quinine  must,  of 
course,  be  discontinued.  Nitrite  of  amyl  and  nitroglycerine, 
with  tonics,  are  recommended. 

Substitutes  for  Quinine. — In  the  treatment  of  malaria 
there  is  no  other  drug  that  can  compare  in  efficacy  to  the  salts 
of  quinine ;  nevertheless,  in  rare  instances,  it  becomes  necessary 
on  account  of  idiosyncras)'-  to  resort  to  the  use  of  other  reme- 
dial agents. 

Of  the  newer  preparations  of  quinine,  euquinine,  saloquinine, 
aristochin,  etc.,  while  purported  to  be  free  from  the  toxic 
properties  of  the  official  salts,  the  writer  has  seen  i  case  in 
which  euquinine  caused  distressing  dyspnea,  and  another  case 
in  which  this  preparation  caused  violent  urticaria.  Euqui- 
nine is  probably  the  most  valuable  of  these  preparations. 

The  alkaloids  of  cinchona,  other  than  quinine,  are  now  but 
rarely  employed,  and  opinions  vary  widely  as  to  their  merits. 
Cinchonidine  is  probably  the  most  useful  of  these  alkaloids. 
It  must  be  given  in  doses  about  twice  as  large  as  of  quinine. 
These  alkaloids,  especially  cinchonine  and  quinidine,  are  more 
toxic  than  quinine,  producing  nervous  and  gastric  disorder 
and,  in  toxic  doses,  convulsions. 

In  order  to  determine  the  value  of  these  alkaloids  in  the 
treatment  of  malaria  the  English  Government,  in  India,  in 
1866,  appointed  a  commission  to  investigate  the  subject.161 


TREATMENT  373 

410  patients  were  treated  with  cinchonine,  of  which  400  were  cured 
350  patients  were  treated  with  cinchonidine,  of  which  346  were  cured 
375  patients  were  treated  with  quinidine,        of  which  365  were  cured 

These  results  are,  however,  much  better  than  those  obtained 
by  other  observers. 

Good  results  have  been  obtained  with  Warburg's  tincture. 
It  is  claimed  that  quinine  may  be  given  in  this  form  when  not 
tolerated  otherwise.  The  liquid  contains,  among  its  many  in- 
gredients, about  10  grains  of  quinine  to  the  ounce,  and  the 
dose  is  j4  ounce  repeated  in  two  to  four  hours.  It  is  prob- 
able that  as  good  effects  can  be  obtained  by  quinine  alone 
in  solution  as  with  this  unpalatable  and  unscientific  conglomera- 
tion of  "quinine  concealed  in  a  farrago  of  inert  substances  for 
purposes  of  mystification."  Its  composition  was  for  a  long 
time  a  secret. 

M ethyl ene-blue  was  introduced  into  the  treatment  of  malaria 
by  Guttmann  and  Ehrlich430  in  1891. 

In  the  writer's  experience  this  is  the  best  substitute  for  the 
derivatives  of  Peruvian  bark.  While  it  does  not  compare 
favorably  with  quinine,  requiring  a  longer  time  to  effect  a 
cure,  and  failing  altogether  in  not  a  few  instances,  it  seems  to 
possess  some  specific  action  upon  the  parasites  of  malaria, 
and  is  the  most  valuable  drug  where  the  cinchona  preparations 
are  absolutely  contra-indicated.  Wood431  collected  from  the 
literature  425  cases  of  malaria  treated  with  methylene-blue 
with  362  cures.  De  Blasi432  tried  it  in  100  cases  with  62  cures. 
Ruge158  considers  methylene-blue  as  efficacious  as  quinine 
against  quartan  fever,  or  even  more  so  under  some  circum- 
stances. Koch33  had  good  results  in  the  cases  in  which  he 
tried  the  remedy,  and  commends  its  use  in  cases  where  quinine 
cannot  be  taken.  Ziemann,48  F.  Plehn,5  Laveran,1  and  others 
have,  however,  had  poor  results  with  the  use  of  methylene- 
blue. 

Only  the  purest  preparation  should  be  employed  for  medici- 
nal purposes,  otherwise  untoward  results  may  follow. 

The  dose  is  from  i1/*  to  3  grains  given  every  three  hours 
until  from  yy2  to  15  grains  have  been  given  in  twenty-four 
hours.    The  drug  may  be  continued  in  this  manner  for  several 


374  THE    STUDY    OF   MALARIA 

days.  Ruge158  has  given  as  much  as  15  grains  daily  for  four 
weeks  without  bad  results.  It  is  best  given  in  capsules.  Kunst90 
injected  subcutaneously  5  cc.  of  a  5  per  cent,  solution ;  in  some 
cases  he  gave  even  as  much  as  1  gram  in  this  manner.  In  the 
latter  cases  the  patients  became  greenish-blue  all  over,  the 
injection  site  remained  painful  for  ten  days  and  became  par- 
tially gangrenous. 

It  is  believed  by  some  observers  that  methylene-blue  has 
more  decided  curative  effect  upon  chronic  than  upon  acute 
malaria.  It  is  probably  most  effective  in  tertian  and  quartan 
infections  than  in  estivo-autumnal.  It  is  thought  that  methyl- 
ene-blue affects  especially  the  plasma  of  the  parasites,  and  is 
consequently  most  effective  in  the  stage  where  this  cell  element 
abounds.  The  drug  causes  a  diminution  of  ameboid  motion  of 
the  parasites  and  a  splitting  of  the  plasma  substance  into  sev- 
eral spheric  masses. 

Untoward  symptoms  caused  by  the  administration  of  methyl- 
ene-blue are  headache,  nausea,  vomiting,  diarrhea,  strangury, 
and  albuminuria.  These  effects  are  less  apt  to  supervene  when 
a  pure  article  is  given.  De  Blasi432  is  of  the  opinion  that  it 
causes  contractions  of  the  pregnant  uterus.  The  addition  of 
2  or  3  grains  of  powdered  nutmeg  lessens  the  tendency  to 
strangury.  The  patient  should  always  be  forewarned  of  the 
blue  color  imparted  to  the  urine  and  feces. 

Thayer433  reached  the  following  conclusions  after  using 
methylene-blue  in  a  few  cases : 

1.  Methylene-blue  has  a  definite  action  against  malarial 
fever,  accomplishing  its  end  by  destroying  the  specific  organ- 
ism ;  but  it  is  materially  less  efficacious  than  quinine,  failing  to 
accomplish  its  purpose  in  many  cases  where  quinine  acts  satis- 
factorily. 

2.  The  action  appears  to  be  rapid,  the  chills  disappearing  or 
the  temperature,  in  the  remittent  cases,  falling  to  normal  dur- 
ing the  first  four  or  five  days ;  but  later,  however,  if  a  sufficient 
number  of  organisms  have  resisted  the  drug,  they  appear  to 
develop  again  directly  under  its  influence,  causing  a  return  of 
the  symptoms. 


TREATMENT  375 

3.  Methylene-blue  seems  to  have  no  advantages  over  quinine 
which  would  warrant  its  further  use. 

Moore  and  Allison,434  who  treated  10  cases  of  malaria  with 
20  grains  daily  of  methylene-blue,  give  the  following  as  their 
conclusions : 

1.  Methylene-blue  will  destroy  malarial  parasites  in  many 
cases,  but  is  less  certain  than  quinine. 

2.  Methylene-blue  is  probably  most  valuable  in  chronic  cases, 
but  has  no  advantage  over  quinine. 

3.  The  effects  of  methylene-blue  are  ordinarily  more  un- 
pleasant than  quinine. 

4.  It  is  useful  in  cases  that  cannot  take  quinine  on  account 
of  some  idiosyncrasy  toward  it.  Its  use  in  cases  of  pregnancy 
is  undetermined. 

5.  It  is  probably  valuable  in  treating  hematuric  and  hemo- 
globinuric  fevers  on  account  of  its  diuretic  action ;  this  has  as 
yet  to  be  determined.  We  have  had  no  chance  to  test  its  use 
in  such  cases. 

6.  We  believe  that  quinine  is  quicker  and  more  certain,  and 
would  rely  upon  it  rather  than  upon  methylene-blue. 

After  its  introduction  in  1842  by  Boudin  arsenic  enjoyed, 
until  recently,  considerable  reputation  in  the  treatment  of 
malaria.  The  old  school  of  physicians  claimed  results  but 
little  inferior  to  those  with  quinine.  More  recent  observations 
show  that  if  this  agent  has  any  value  in  the  treatment  of 
malaria  it  is  in  the  chronic  form.  Whether  its  good  effects 
here  are  chiefly  upon  the  anemia  and  as  a  general  tonic  or 
whether  it  has  some  action  upon  the  parthenogenetic  cycle  is 
not  determined.  Fowler's  solution  and  the  arsenous  acid  are 
the  preparations  usually  employed.  The  dose  at  the  beginning 
should  be  small  and  gradually  increased.  Upon  the  appearance 
of  puffiness  of  the  eyelids,  colicky  pains  in  the  abdomen,  and 
diarrhea  the  dose  should  be  diminished  or  its  use  temporarily 
discontinued.  The  arsenous  acid  may  well  be  combined  with 
iron,  quinine,  and  strychnine  in  the  treatment  of  chronic 
malaria. 

Two    recent   preparations   of   arsenic,    arrhenal   or   disodic 
methylarsenate,  and  sodium  cacodylate  have  been  vaunted  as 


376  THE    STUDY    OF    MALARIA 

antimalarials  by  Gautier  and  others.  They  are  rich  in  arsenic, 
but  less  toxic.  Both  preparations  have  been  used  in  cases 
where  abortion  threatened,  and  good  results  have  been  claimed. 
They  are  usually  given  hypodermically  in  doses  of  from  24  to 
1Y2  grains  daily. 

The  benefits  derived  from  atoxyl  in  the  treatment  of  trypano- 
somiasis led  to  an  investigation  of  its  merits  in  malaria. 
Chemically,  atoxyl  is  sodium  aminophenyl  arsenate,  containing 
about  25  per  cent,  of  arsenic  and  soluble,  at  20°  C,  in  4.3 
parts  of  water.  The  usual  dose  is  from  one-third  to  1 
grain,  given  every  day  or  every  other  day,  usually  hypodermic- 
ally. 

Grosch435  cured  with  atoxyl  a  case  of  malaria  that  obstinately 
resisted  quinine  for  a  long  period.  Fusco  had  satisfactory  re- 
sults in  3  cases.  Koch,  in  reporting  his  experience  with  atoxyl 
in  the  treatment  of  sleeping  sickness,  states  that  in  cases  that 
were  complicated  with  malaria,  usually  of  the  estivo-autumnal 
variety,  the  malarial  parasites  diminished  markedly,  but  were 
not  so  decidedly  influenced  by  the  drug  as  were  the  trypano- 
somes. 

Slatineano  and  Galesesco,  employing  large  doses  of  atoxyl 
in  15  cases  of  malaria,  had  10  cures  and  5  failures.  The  fail- 
ures were  experienced  mostly  with  double  infections.  Georg- 
opulos,  after  its  use  in  14  cases,  reported  that  the  paroxysms 
ceased,  the  spleen  diminished  in  size,  the  parasites  disappeared 
from  the  blood,  and  the  general  condition  of  the  patient  im- 
proved. In  6  cases  treated  by  Gonder  and  Dapas  the  patients 
improved  during  the  treatment ;  in  2  cases  the  splenic  enlarge- 
ment diminished  considerably,  but  in  only  1  case  did  the  para- 
sites disappear  entirely.  The  resistance  of  the  gametes,  espe- 
cially the  macrogametes,  to  the  drug  was  noteworthy.436  Vas- 
sal437 claims  good  results,  especially  in  malarial  cachexia,  by 
the  use  of  atoxyl  with  the  quinine. 

While  the  experience  of  the  writer  with  atoxyl  has  been 
limited,  he  believes  that  it  is  a  valuable  adjuvant  to  quinine  in 
the  cases  where  the  latter  is  insufficient,  particularly  in  cases 
of  cachexia  and  extreme  anemia.  Its  good  effect  in  these  cases 
may  be  due  to  the  increased  amount  of  arsenic  which  may  be 


TREATMENT  377 

administered  in  this  form.  In  employing  atoxyl  its  possible 
toxic  effects  should  not  be  lost  sight  of. 

The  value  of  opium  in  the  treatment  of  malaria  was  discov- 
ered accidentally  by  Lind,71  in  1766.     He  says: 

"The  effects  of  opium  given  in  the  hot  fit  of  an  intermit- 
ting fever  are :  ( 1 )  It  shortens  and  abates  the  fit,  and  this, 
with  more  certainty  than  an  ounce  of  bark,  is  found  to  remove 
the  disease;  (2)  it  generally  gives  a  sensible  relief  to  the  head, 
takes  off  the  burning  heat  of  the  fever,  and  occasions  a  profuse 
sweat;  this  sweat  is  attended  with  an  agreeable  softness  of 
the  skin  instead  of  the  disagreeable  burning  sensation  which 
usually  affects  patients  sweating  in  the  hot  fit,  and  is  more 
copious  than  in  those  who  are  not  under  the  influence  of  opium ; 
(3)  it  often  produces  a  soft  and  refreshing  sleep  to  patients 
before  harassed  with  the  fever,  from  which  they  awake  bathed 
in  sweat,  and  in  a  great  measure  free  from  complaint. 

"I  have  always  observed  that  the  effects  of  opium  are  more 
uniform  and  constant  in  intermitting  fevers  than  in  most  other 
diseases,  and  are  then  more  quick  and  sensible  than  those  of 
most  other  medicines.  An  opiate  thus  given,  soon  after  the 
commencement  of  the  hot  fit,  by  abating  the  violence  and  less- 
ening the  duration  of  the  fever,  preserves  the  constitution  in 
a  great  measure  uninjured.  Since  I  have  used  opium  in  agues, 
a  dropsy  or  jaundice  has  seldom  attacked  any  of  my  patients  in 
these  diseases." 

Opium  is  not  only  effective  against  certain  symptoms  of 
malaria,  but  it  has  been  shown  by  Drake65  and  others  to  possess 
antiperiodic  virtue.  This  is,  in  all  probability,  due  to  the 
narcotine  contained.  For  this  reason  opium,  in  the  form  of 
the  powder,  Dover's  powder,  laudanum,  or  paregoric,  is  more 
effective  than  morphine.  In  order  to  test  the  value  of  narcotine 
as  compared  to  quinine,  Duncan438  treated  78  cases  of  malaria 
with  quinine,  with  an  average  duration  of  fever  of  2. 11  days 
and  20.5  per  cent,  of  failures;  with  66  cases  of  malaria  treated 
with  narcotine  the  average  duration  of  the  fever  was  2.77  days 
and  the  per  cent,  of  failures  only  1.06.  The  immunity  of 
opium  smokers  to  malaria  has  been  remarked  upon  by  a  num- 
ber of  tropic  physicians. 


378  THE    STUDY   OF    MALARIA 

A  large  number  of  other  substances  have  been  recommended 
as  substitutes  for  quinine.  The  chief  of  these  are  phenocoll, 
eucalyptus,  salicin,  salicylic  acid,  sodium  hyposulphite,  etc. 
Their  antimalarial  value,  if,  indeed,  they  possess  any,  is  so 
slight  as  to  render  a  detailed  consideration  not  worth  the 
while. 

The  serum  treatment  of  malaria  has  not  yet  reached  the 
stage  of  practical  utility.  Indeed,  the  experiments  of  Ford140 
alone  have  resulted  in  the  isolation  of  an  antitoxin.  In  his 
first  series  of  9  cases  of  benign  tertian  malaria  7  were  cured, 
1  was  temporarily  benefited,  while  in  the  other  the  result  was 
negative.  In  his  second  series  of  20  cases  of  benign  tertian 
17  were  cured,  while  3  were  apparently  quite  uninfluenced. 

Critzmann86  had  several  cachectic  patients  eat  three  times 
daily  50  grams  of  chopped  beef  spleen  mixed  with  the  yolk 
of  an  egg  and  10  grams  of  bone-marrow.  Burot  and  Le- 
grand225  used  the  same  treatment  in  numerous  cases  of  cachexia 
in  the  hospital  of  Rochefort.  In  the  course  of  about  fifteen 
days  the  patient  acquired  a  disgust  for  the  repast.  While  the 
preparation  had  no  effect  upon  the  fever,  it  seemed  to  act  as 
a  reconstituent. 

More  recently  Carpenter439  claims  remarkable  success  in  the 
treatment  of  malaria  with  powdered  splenic  extract  in  the  dose 
of  5  grains  every  two  to  four  hours,  preferably  in  capsules. 
He  says :  "In  more  than  six  years'  continuous  experience  and 
in  the  treatment  of  hundreds  of  cases  of  malarial  infections 
of  all  types,  both  simple  and  complicated  by  all  sorts  of  condi- 
tions, not  a  single  case  has  been  met  with  which  did  not  yield 
to  this  remedy."  He  further  states  that  it  is  equally  as  reliable 
a  remedy  as  quinine. 

The  Treatment  of  Pernicious  Malaria. — There  are  cer- 
tain cases  apparently  on  the  borderline  between  benign  malaria 
and  pernicious  malaria  of  the  cerebral  type  which  may  cause 
hesitation  as  to  the  mode  of  administration.  In  these  cases, 
usually  in  children,  the  patients,  though  stupefied,  or  even  semi- 
comatose, can  be  aroused  and  made  to  swallow  and  usually 
retain  the  medicine.  In  such  cases,  if  the  patient  can  be 
watched,  the  quinine  may  be  given  in  solution  by  the  mouth. 


TREATMENT 


379 


If  vomited  or  if  the  symptoms  do  not  rapidly  improve,  the  drug 
in  dilute  solution  should  be  injected  intramuscularly.  Where 
the  injection  mode  is  chosen  it  is  advisable  to  supplement  this 
with  oral  administration  of  the  solution  where  it  can  be  swal- 
lowed, and  even  the  rectum  may  be  employed  also. 

As  previously  stated,  quinine  for  intramuscular  injection 
should  be  in  dilute  solution;  15  grains  to  2.y2  drams  of  water 
is  a  suitable  proportion.  The  gluteal  region,  above  the  ischial 
tuberosities,  is  the  best  site  for  injection.  In  pernicious  cases 
about  15  grains  is  the  quantity  to  be  used  at  first  injection. 
Subsequent  doses  may  be  from  5  to  10  grains  injected  every 
six  to  eight  hours  as  needed.  The  technic  of  such  injections 
has  already  been  given. 

Just  as  antisyphilitics  may  cause  the  gumma  to  melt  rapidly 
but  are  powerless  to  restore  the  tissue  it  has  destroyed,  so 
quinine  has  its  limitations  in  the  therapeutics  of  malaria.  It 
should  be  borne  in  mind  that  in  its  relation  to  the  parasites 
quinine  is  a  toxin,  but  not  an  antitoxin.  It  is  possible  that 
where  the  parasites  are  accumulated  to  the  extent  of  throm- 
bosis the  quinine  in  solution  in  the  blood  does  not  reach  them 
in  toxic  quantities,  and  where  perivascular  exudation,  hemor- 
rhage, and  necrosis  have  resulted  from  these  thrombi  the  anni- 
hilation of  the  parasites  avails  nothing.  This  is  corroborated 
by  those  cases  ending  fatally,  notwithstanding  a  rapid  disap- 
pearance of  the  parasites,  and  in  which  post  mortem  these 
secondary  changes  are  found.  All  that  can  be  expected  of 
quinine  is  to  destroy  the  parasites,  and  this  it  may  fail  to 
accomplish  from  not  being  absorbed  or  not  being  present  in 
the  blood  in  sufficient  quantities  or  at  the  time  when  the  para- 
sites are  most  susceptible  to  its  action,  or  on  account  of  throm- 
botic occlusions  it  may  not  gain  access  to  the  parasites  causing 
the  symptoms.  Quinine  is  probably  a  true  specific  in  those 
cases  of  pernicious  malaria  only  in  which,  in  the  absence  of 
irreparable  changes  due  to  toxins  or  to  thrombi,  the  prompt 
destruction  of  the  parasites  would  be  attended  by  an  almost 
simultaneous  cessation  of  symptoms. 

Other  than  the  specific  treatment  there  are  important  symp- 
tomatic indications  to  be  met. 


380  THE    STUDY   OF    MALARIA 

In  cases  with  high  temperature  and  hot  dry  skin  cooling 
baths  should  be  used.  For  heart  depression  strychnine  or 
digitalis  are  useful. 

In  the  cerebral  types  the  ice-bag  to  the  head  is  called  for 
and  an  active  cathartic  should  be  given  if  possible.  Where  this 
cannot  be  swallowed,  a  drop  of  croton  oil  on  the  back  of  the 
tongue  may  be  tried.  If  delirium  is  marked,  a  solution  of 
chloral  and  the  bromides  should  be  given  by  the  rectum.  Where 
there  are  convulsions,  chloral  and  bromides  by  the  rectum, 
morphine  hypodermically,  or  even  inhalations  of  chloroform 
may  be  necessary.  Bell  employed  lumbar  puncture  in  a  case 
of  malarial  coma  to  relieve  the  increase  in  the  cerebrospinal 
fluid  which  usually  exists  in  these  cases,  but  the  result  was 
disappointing. 

In  algid  attacks  for  the  relief  of  cold  surface  and  dyspnea, 
especially  if  choleraic  symptoms  are  present,  nothing  is  so  suit- 
able as  a  combination  of  morphine  and  atropine.  The  heart 
usually  requires  stimulation  by  strychnine  and  digitalis.  Hypo- 
dermics of  ether  may  be  necessary.  If  dysenteric  symptoms 
arise  they  should  be  treated  with  opium  and  bismuth,  together 
with  saline  irrigations. 

If  complications  appear  they  should  receive  appropriate 
treatment. 

During  convalescence  a  tonic  of  arsenic,  strychnine,  iron, 
and  quinine  is  usually  indicated.  In  cases  where  it  is  feasible, 
a  change  of  climate  should  be  ordered  until  recovery  is  thor- 
oughly established. 

Treatment  of  Hemoglobinuric  Fever. — The  discussion  of 
the  treatment  of  hemoglobinuric  fever  has  probably  been  pro- 
ductive of  more  harsh  and  prejudiced  controversies  than  has 
any  other  question  in  therapeutics.  The  bone  of  contention 
is  quinine. 

It  is  unnecessary  to  review  the  history  of  the  discussions 
or  to  rehearse  the  arguments  for  or  against  the  etiologic  rela- 
tion of  quinine  to  blackwater  fever.  No  valid  conclusion  can 
be  reached  except  through  results  of  a  large  series  of  cases 
treated  with  and  without  quinine.  The  collection  recorded 
under  Prognosis  shows  a  mortality  of  25.9  per  cent,  in  cases 


TREATMENT  381 

treated  with  quinine,  and  ii.i  per  cent,  in  cases  in  which  no 
quinine  was  used.  This  number  of  cases  probably  eliminates 
all  errors  and  should  be  convincing. 

While  the  results  of  the  series  prove  that  the  mortality  is 
higher  under  the  routine  treatment  with  quinine,  they  should 
not  be  taken  to  exclude  absolutely  the  use  of  quinine  in  some 
cases  of  hemoglobinuric  fever,  for  under  certain  circumstances 
quinine  may  be  of  value.  It  is  difficult — in  fact,  sometimes 
impossible — to  say  whether  quinine  is  indicated  or  contraindi- 
cated  in  a  certain  case. 

Mannaberg1411  gives  the  following  general  rules  to  aid  a 
decision : 

1.  When,  without  quinine  preceding,  hemoglobinuria  oc- 
curs and  the  blood  examination  shows  the  presence  of  malarial 
infection,  quinine  is  undoubtedly  to  be  exhibited. 

2.  When  the  hemoglobinuria  occurs  after  one  dose  of 
quinine,  while  the  anamnesis  shows  that  the  patient  previously 
took  quinine  without  bad  effect,  and  the  parasites  are  present 
in  the  blood,  quinine  is  also  to  be  exhibited.  If  a  paroxysm 
of  hemoglobinuria  should  follow  within  a  few  hours,  the  repe- 
tition of  the  drug  should  be  made  dependent  upon  whether  or 
not  the  parasites  have  in  great  part  disappeared.  In  the  former 
case  the  quinine  may  be  stopped,  at  least  for  a  time.  But  if 
the  blood  examinations  show  that  the  parasites  have  increased 
in  number  the  quinine  is  to  be  continued. 

3.  When  the  anamnesis  shows  that  the  patient  suffered  pre- 
viously from  hemoglobinuria  following  quinine  and  the  blood 
examination  is  negative,  quinine  is  to  be  absolutely  avoided. 

4.  When  the  case  manifests  a  severe  malarial  infection 
(numerous  parasites  on  examination)  and  at  the  same  time  an 
assured  intolerance  to  quinine  in  the  shape  of  hemoglobinuria 
the  decision  is  very  difficult. 

Marchiafava  and  Bignami22  believe  that  the  only  guide  indi- 
cating to  the  physician  whether  to  give  or  to  withhold  quinine 
ought  to  be  the  result  of  a  blood  examination. 

Bastianelli's101  canon  is  as  follows : 

1.  If  a  hemoglobinuria  occurs  during  a  malarial  paroxysm 
and  parasites  are  found  in  the  blood  quinine  should  be  given. 


382  THE    STUDY   OF    MALARIA 

2.  If  parasites  are  not  found  in  the  blood  quinine  should  not 
be  given. 

3.  If  quinine  has  already  been  given  before  the  hemoglo- 
binuria has  appeared  and  no  parasites  are  found,  its  use  should 
be  suspended ;  but  if  parasites  persist  it  should  be  continued. 

Thayer98  states  his  rules,  modified  from  Bastianelli,  thus : 

1.  If  the  attack  occurs  spontaneously  with  a  malarial  parox- 
ysm, the  blood  showing  the  presence  of  parasites,  quinine 
should  be  freely  administered  hypodermically  or  intravenously. 

2.  If  the  parasites  have  disappeared,  either  as  a  result  of 
the  paroxysm  itself  or  of  doses  of  quinine  already  given,  it 
may  be  as  well  to  abstain,  at  least  for  a  time,  from  the  admin- 
istration of  the  drug.  It  cannot  ameliorate  the  further  course 
of  the  paroxysm,  and  the  possibility,  if  it  has  been  already 
given,  that  the  symptoms  may  be  in  part  due  to  quinine  may 
be  thought  of. 

3.  If  an  attack  arise  in  the  middle  of  an  ordinary  malarial 
infection,  after  taking  quinine,  it  is  best  to  abstain,  for  a  time, 
at  any  rate,  from  the  further  use  of  the  drug.  That  which  has 
been  given  may  have  been  enough  to  control  the  affection. 

4.  If,  however,  in  an  attack  coming  on  after  quinine,  the  par- 
asites continue  to  develop,  quinine  should  be  again  adminis- 
tered, despite  the  slight  possibility  of  its  injurious  action.  The 
dangers  from  the  further  development  of  the  parasites  are 
probably  the  greater. 

5.  In  postmalarial  hemoglobinuria  quinine  is,  of  course,  use- 
less. 

The  following  rules  of  Vedy213  are  practical : 

1.  If  living  parasites  (not  merely  evidence  of  their  former 
existence,  pigment)  are  detected  twenty-four  hours  after  the 
beginning  of  the  attack  80  centigrams  of  a  salt  of  quinine 
may  be  injected  subcutaneously. 

2.  If  the  parasites  are  not  visible  do  not  administer  quinine. 

3.  If  in  doubt,  that  is  to  say,  if  the  microscopic  examination 
of  the  blood  cannot  be  made,  do  not  give  quinine. 

It  may  be  seen  that  the  authorities  quoted  lay  great  stress 
on  the  presence  of  the  parasite  as  a  guide  to  the  administration 
of  quinine.    The  writer,  however,  cannot  agree  with  those  who 


TREATMENT  383 

hold  that  quinine  should  be  exhibited  in  every  case  where  the 
microscopic  examination  shows  the  presence  of  parasites.  It 
has  been  shown  conclusively  that  parasites  are  present  in  a 
very  large  proportion  of  cases  examined  early.  It  has  also 
been  shown  that  in  an  equally  large  number  of  cases  the  para- 
sites disappear  spontaneously.  In  these  cases  quinine  is,  to 
say  the  least,  superfluous. 

In  the  writer's  opinion,  the  only  conditions  in  which  quinine 
is  indicated  are:  first,  where  the  parasites  show  no  tendency 
to  disappear  after  forty-eight  hours  from  onset;  second,  in 
the  infrequent  cases  of  intermittent  hemoglobinuria  where  the 
outbreak  corresponds  with  parasitic  sporulation. 

If  it  is  decided  to  give  quinine  it  should  be  injected,  in  dilute 
solution,  into  the  muscles  as  directed  for  the  treatment  of 
pernicious  malaria.  Given  by  the  mouth  it  upsets  the  stomach 
and  may  not  be  absorbed. 

Even  in  cases  of  mildest  onset  the  patient  should  be  confined 
to  bed  from  the  start,  and  should  be  kept  quiet  either  by 
suasion  or  by  sedatives.  Sudden  death  on  slight  exertion  some- 
times occurs.  The  patient  should  not  be  transported  from  one 
place  to  another;  the  Plehn  brothers  observed  anuria  as  a 
frequent  consequence  of  moving  patients  from  place  to  place. 
Chilling  of  the  body,  especially  when  the  temperature  is  low, 
should  be  carefully  avoided.  When  vomiting  is  not  a  promi- 
nent feature  liquid  nourishment  may  be  given  freely;  butter- 
milk and  albumen  water  are  the  most  suitable.  Sweet  milk  is 
often  ejected  as  a  thick  curd,  molded  ropy  by  the  esophagus 
in  the  act  of  vomiting.  Animal  broths,  barley  and  oatmeal 
water,  lemonade,  and  orange  juice  are  allowable.  Rectal  ali- 
mentation is  unsatisfactory. 

There  is  no  specific.  Methylene-blue  has  proved  disappoint- 
ing. Besides  being  a  renal  irritant,  it  masks  the  color  of  the 
urine,  a  most  serious  objection.  Salicylic  acid  probably  has 
no  effect  further  than  to  upset  the  stomach  and  increase  the 
discomfort.  With  the  false  idea  that  a  hemorrhage  has  to  be 
checked,  gallic  and  tannic  acids,  ergot,  and  similar  drugs  are 
frequently  given ;  these  cannot  possibly  be  of  any  benefit.  Car- 
bolic acid  and  other  renal  irritants  should  not  be  used. 


384  THE   STUDY   OF    MALARIA 

The  bowels  should  be  moved  early  and  often,  and  calomel 
possesses  advantages  over  other  purgatives;  it  is  more  easily- 
retained,  is  a  bland  diuretic,  and  is  the  best  of  intestinal  anti- 
septics. Too  large  doses  are  usually  advised;  3  to  5  grains 
are,  as  a  rule,  sufficient,  repeated  pro  re  nata. 

Quennec'si40  chloroform  treatment  has  been  successful  in 
some  hands.  The  originator  claims  for  the  method  three 
points  of  value : 

1.  Controls  vomiting. 

2.  Increases  output  of  urine. 

3.  Diminishes  albuminuria. 

He  treated  more  than  50  cases  with  no  mortality.  The  fol- 
lowing is  his  formula:  Chloroform,  6  grams;  gum  arabic,  8 
grams;  sweetened  water,  250  grams.  This  amount  is  used 
daily,  a  sip  taken  every  ten  minutes.  In  addition,  Quennec 
used  quinine,  1  gram  daily  subcutaneously,  and  sulphate  of 
soda  and  senna  by  rectum.  The  excessive  administration  of 
chloroform  might  be  harmful,  as  it  is  a  cardiac  depressant, 
renal  irritant,  and  lowers  the  blood  pressure. 

Cardamatis206  gives  ether  in  every  case  of  hemoglobinuric 
fever.  In  ordinary  cases  he  prescribes  a  teaspoonful  in  sweet- 
ened water  every  three  hours,  and  increases  the  dose  if  the 
urine  diminishes  in  quantity.  In  cases  of  suppression  he  gives 
as  much  as  a  teaspoonful  every  hour,  at  the  same  time  inject- 
ing hypodermically  1  cc.  every  two  or  three  hours.  He  main- 
tains that  by  this  means  the  pulse  is  strengthened,  precordial 
anxiety,  dyspnea,  and  vomiting  are  relieved,  and  a  profuse 
diuresis  is  provoked. 

The  writer  has  had  no  experience  with  ether  in  the  treatment 
of  blackwater  fever,  but  would  consider  it  too  irritating  to  the 
kidneys  for  general  use. 

Hearsey266  used  with  good  results  a  modification  of  Stern- 
berg's yellow-fever  treatment.  The  original  Sternberg  for- 
mula is:  sodium  bicarbonate,  150  grains;  mercury  perchloride, 
one-third  grain ;  water,  2  pints.  .  Sig. :  1  y2  ounces  every  hour. 
Hearsey  gives  sodium  bicarbonate,  10  grains ;  liquor  hydrargyri 
perchloridi,  30  minims ;  every  two  to  three  hours. 

A  method  of  treatment  recently  introduced  and  extrava- 


TREATMENT  385 

gantly  extolled  by  its  originator  is  that  of  Vincent.**1  This 
writer  maintains  that  calcium  chloride  is  not  only  a  preventive, 
but  has  extraordinary  curative  powers.  During  the  attack  from 
4  to  6  grams  are  given  daily  by  the  mouth,  or  from  i  to  2 
grams  dissolved  in  normal  salt  solution  hypodermically.  He 
asserts  that  it  acts  as  an  antihemolysin,  and  that  in  persons  in 
whom  an  attack  of  blackwater  may  be  provoked  at  will  by 
a  dose  of  quinine,  the  previous  administration  of  calcium  chlo- 
ride will  forestall  the  outbreak.  It  is  worthy  of  mention  that 
this  drug  has  been  used  successfully  in  paroxysmal  hemoglo- 
binuria by  Saundby,  and  in  hemophilia  by  Wright  and  others. 

The  writer  has  recently  employed  calcium  chloride  in  6 
cases,  of  which  3  ended  fatally.  The  series  is  too  small  to 
permit  of  very  definite  conclusions  as  to  results  of  treatment, 
but  it  would  appear  that  the  results  claimed  by  Vincent  were 
not  obtained.  The  3  fatal  cases  were  in  persons  whose  health 
was  probably  not  more  undermined  from  previous  malaria  or 
other  causes  than  the  average  patient  who  is  attacked  with 
hemoglobinuric  fever.  It  is  worthy  of  note  that  the  cause 
of  death  in  these  3  cases  was  not  syncope  nor  suppression, 
but  exhaustion  due  directly  to  hemolysis,  the  very  process 
which  calcium  chloride  was  used  to  combat.  No  treatment 
other  than  supportive  was  used  which  might  modify  the  anti- 
hemolytic  effects  of  the  calcium  chloride. 

Hyposulphite  of  soda  introduced  into  the  treatment  of  mala- 
rial conditions  by  Polli,442  in  1867,  has  been  used  extensively 
in  the  treatment  of  hemoglobinuria.  Its  use  is  probably  not 
attended  with  any  signal  results.  O'Sullivan-Beare443  used 
with  good  results  a  decoction  of  the  root  of  cassia  beareana, 
a  native  plant.  Gouzien  employed  an  infusion  of  the  leaves 
of  cassia  occidentalis. 

Teas  made  from  the  leaves  of  folia  combreti  alti  and  of 
aphloia  theceformis  are  also  highly  recommended.86 

The  fever  does  not  usually  run  sufficiently  high  to  call  for 
treatment.  The  coal-tar  preparations  should  be  assiduously 
avoided.  Cold  baths  may  be  productive  of  harm  by  increasing 
the  blood  destruction,  but  in  hyperpyrexial  cases  sponging  with 
tepid  water  may  be  resorted  to. 

25 


386  THE   STUDY   OF   MALARIA 

Vomiting,  if  not  intense,  is  often  benefited  by  a  mustard 
plaster  on  the  epigastrium.  The  fly-blister  formerly  used 
should  be  abandoned.  Draughts  of  hot  water  or  carbonated 
water  sometimes  assist  in  relieving  this  troublesome  symptom. 
Cracked  ice  may  be  tried.  Morphine  hypodermically  should 
be  given  unhesitatingly  when  other  measures  fail.  Any  evil 
effects  are  more  than  outweighed  by  its  enabling  the  stomach 
to  retain  liquids. 

An  important  measure  toward  the  prevention  and  relief  of 
nausea  and  vomiting  is  to  maintain  the  recumbent  position. 
Medicine,  water,  and  nourishment  should  be  taken  through 
a  drinking  tube  or  the  ordinary  invalid's  cup,  and  the  bed- 
pan or  urinal  should  be  used  when  evacuating  the  bowels  or 
bladder. 

It  is  imperative  to  allay  the  restlessness  often  present  in  these 
cases.  For  this  purpose  chloral  and  bromide  of  soda  by 
rectum,  morphine  hypodermically,  or  sulphonal  or  small  doses 
of  chloroform  by  mouth  are  useful. 

Probably  the  most  important  indication  in  the  treatment  is 
the  prevention  of  suppression.  Medicinal  diuretics  usually  do 
harm.  One,  turpentine,  widely  used  in  some  sections,  should 
be  condemned  in  the  strongest  terms.  It  is  one  of  the  most 
violent  renal  irritants,  and  in  some  persons  small  doses  may 
cause  suppression  or  hematuria.  Water  is  the  best  diuretic, 
and  as  much  should  be  given  by  mouth  as  will  be  retained. 
Lewis,1,92  of  North  Carolina,  was  the  first  to  recommend  the 
use  of  normal  salt  solution  by  hypodermoclysis  and  by  the 
rectum  in  the  treatment  of  hemoglobinuric  fever,  though  Lav- 
eran1  attributes  the  priority  to  Gouzien.  The  latter  recom- 
mends the  daily  injection  of  100  to  300  grams  of  a  nine-tenths 
per  cent,  solution,  in  conjunction  with  the  rectal  injection  of 
200  grams,  four  to  six  times  in  twenty-four  hours.  The  use 
of  salt  solution  is  the  very  best  means  of  combating  and  treat- 
ing anuria.  It  is  probably  better  to  use  a  hypertonic  solution. 
In  mild  cases  where  the  urine  is  free  the  rectal  use  is  usually 
sufficient,  but  in  cases  where  suppression  threatens  or  is  immi- 
nent the  solution  should  be  used  subcutaneously  or  intra- 
venously and  in  larger  quantities  and  oftener  than  advised  by 


TREATMENT  387 

Gouzien.  Mild  counterirritation  over  the  region  of  the  kidneys 
may  be  tried. 

Werner,444  in  1902,  suggested  nephrotomy  for  anuria.  Such 
an  operation  has  been  recorded  in  only  three  instances.  Zie- 
mann48  mentions  a  case  in  a  young  female  patient  in  whom 
suppression  had  existed  two  days.  The  capsule  of  the  right 
kidney  was  split  and  peeled  off  to  the  hilum  and  nephrotomy 
performed  through  the  convexity  of  the  organ.  The  operation 
was  well  borne,  and  subsequently  200  cc.  of  cloudy,  albuminous 
urine  was  voided  from  the  bladder.  During  the  following 
days  complete  suppression  recurred,  and  the  patient  died. 

In  Kruger's445  case  decortication  of  one  kidney  was  done 
five  days  after  the  onset  of  anuria,  and,  although  the  secretion 
of  urine  was  profusely  reestablished,  the  patient  died  of  pro- 
gressive weakness. 

Kiilz446  reports  a  case  in  a  man  during  his  second  attack. 
Three  and  a  half  days  after  the  onset  of  anuria  nephrotomy 
upon  one  kidney  was  performed  through  Simon's  incision. 
Vomiting,  which  was  formerly  uncontrollable,  ceased  imme- 
diately. Three  hours  after  the  operation  30  cc.  of  blood  were 
voided  from  the  bladder.  In  eight  hours  the  dressing  was 
saturated  with  bloody  icteric  urine,  which  necessitated  chang- 
ing the  dressing  every  three  hours.  Twenty-four  hours  after 
the  operation  the  patient  died.  Though  a  microscopic  examina- 
tion of  the  kidney  could  not  be  made,  upon  gross  inspection 
the  nephrotomized  kidney  appeared  much  more  nearly  normal 
than  the  other. 

Supportive  measures  are  essential.  Alcohol  in  all  its  forms 
is  inadmissible.  Strychnine  is  useful,  and  should  be  given 
hypodermically  when  circumstances  permit.  Digitalis  has 
proved  serviceable  in  the  writer's  hands.  Doering187  had  good 
effects  from  strophanthus.  The  aromatic  spirits  of  ammonia 
and  hypodermic  injections  of  ether  have  been  recommended. 
Transfusion  of  blood  has  been  used,  it  is  said,  with  excellent 
results.  The  elder  Plehn61'  says  that  he  had  four  attacks,  in 
which  Kohlstock  treated  him  with  inhalations  of  oxygen,  and 
that  nothing  else  did  him  so  much  good.  Unfortunately,  this 
method  of  treatment  is  not  often  possible  in  private  practice. 


388  THE   STUDY   OF  MALARIA 

The  after-treatment  should  have  a  care  for  the  diet,  which 
should  be  non-nitrogenous  and  consist  largely  of  liquids  at 
first.  A  tonic  of  organic  iron  is  indicated,  and  digestive  dis- 
orders when  present  should  receive  appropriate  treatment. 

A  question  of  practical  importance  is,  how  soon  after  the 
attack  to  begin  the  administration  of  quinine.  A  dose  given 
too  early  might  possibly,  in  some  persons,  precipitate  hemol- 
ysis. On  the  other  hand,  delay  may  permit  an  outbreak  of 
malaria  accompanied  by  hemoglobinuria.  Upon  the  ground 
that  most  of  the  sensitive  cells  have  succumbed  during  the  at- 
tack and  that  the  newly  formed  cells  are  probably  more  sus- 
ceptible than  those  that  have  withstood  the  attack,  the  writer 
is  of  the  opinion  that  quinine  should  be  begun,  carefully  at 
first,  a  short  time  after  the  attack  has  subsided  and  before 
blood  regeneration  is  fairly  established.  One  grain  of  quinine 
three  times  daily,  increased  gradually  every  other  day,  is  a 
safe  procedure.  If  the  temperature  rises  or  the  urine  becomes 
distinctly  darker  no  further  attempt  to  increase  the  dose  should 
be  made. 

In  the  present  state  of  our  knowledge  it  is  probably  Utopian 
to  discuss  the  treatment  of  hemoglobinuric  fever  by  antihemo- 
lytic  sera,  but  such  has  recentfy  been  successfully  accomplished 
by  Widal  and  Rostaine447  in  paroxysmal  hemoglobinuria. 

REFERENCES 

1.  Laveran:  Traite  du  Paludisme,  Paris,  1907. 

2.  New  Orleans  Med.  and  Surg.  Jour.,  iv,  563,  1848. 

3.  King:  Popular  Science  Monthly,  Sept.,  1883. 

4.  Crosse :  Blackwater  Fever,  London,  1899. 

5.  Plehn:  Die  Kamerun  Kiiste,  Berlin,  1898. 

6.  Mense :  Arch,  fiir  Schiffs.-  u.  Trop.  Hyg.,  iii,  4. 

7.  Kohlbrugge :  Arch,  fiir  Schiffs.-  u.  Trop.  Hyg.,  iii,  2. 

8.  Cited  by  Mense  (6). 

9.  Sambon :  The  Practitioner,  March,  1901. 

10.  Cited  by  Sternberg  (73). 

11.  Cummings :  N.  O.  Med.  News  and  Hosp.  Gaz.,  vi,  811. 

12.  Faget :  N.  O.  Med.  Jour.,  Oct.,  1868. 

13.  Osborne :  Ibid.,  1868,  644. 

14.  Osborne:  Ibid.,  xxii,  61. 

15.  Ghent:  Richmond  and  Louisville  Med.  Jour.,  v,  271. 

16.  Cited  by  Cardamatis  (206). 

17.  Johnson :  Influence  of  Tropical  Climates,  etc.,  New  York,  1826. 

18.  Cleghorn :  Diseases  of  Minorca,  London,  1762. 

19.  Hirsch :  Handbook  of  Geog.  and  Hist.  Pathology,  London,  1883,  vol.  i. 

20.  Cited  by  Rogers  (44) . 

21.  Ramazzini :  Sur  lAbus  du  Quinquina,  Paris  Reprint,  1905. 


REFERENCES  389 

22.  Marchiafava  and  Bignami :   Malaria,  New  York,  1000. 

23.  Medizinal  Berichte  iiber  die  Deutschen  Schutzgebiete,  1903-04. 

24.  A.  Plehn :  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  vii,  12. 

25.  Moore:  Jour.  Trop.  Med.,  March  15,  1902. 

26.  Curry:  Bost.  Med.  and  Surg.  Jour.,  Nov.  23,  1899. 

27.  Scheube :  Die  Krankheiten  der  Warmen  Lander,  Jena,  1903. 

28.  Charity  Hospital  Reports,  New  Orleans,  1906,  1907. 

29.  Thayer  and  Hewetson :  The  Malarial  Fevers  of  Baltimore,  Baltimore, 

1895. 

30.  Kendall :  Jour.  Am.  Med.  Assoc,  46,  1270. 

31.  Gray  and  Low :  Brit.  Med.  Jour.,  Jan.  25,  1902. 

32.  Gorgas:  Ann.  Rep.  Dept.  Sanitat.  Isthmian  Canal  Commis.,  1907-08. 

33.  Koch :  Deut.  Med.  Woch.,  Feb.  2,  1899. 

34.  Koch :  Deut.  Med.  Woch.,  Sept.  14,  1899. 

35.  Cardamatis  and  Diamessis :  La  Grece  Med.,  Nov.  1-15,  1906. 

36.  Mollow:  Malaria,  vol.  i,  75. 

37.  Atti  Delia  Soc.  per  gli  Studi  della  Malaria,  Rome,  1901-08. 

38.  Wright:  The_  Malarial  Fevers  of  British  Malaya,  London,  1902. 

39.  Craig:  Rev.  in  Jour.  Trop.  Med.,  June  15,  1904. 

40.  Hope:  Jour.  Trop.  Med.,  June  15,  1904. 

41.  Williamson:  Brit.  Med.  Jour.,  Sept.  14,  1901. 

42.  Koch :  Deut.  Med.  Woch.,  April  26,  1900. 

43.  Chamberlain:  Jour.  Am.  Med.  Assoc,  46,  304. 

44.  Rogers :  Fevers  in  the  Tropics,  London,  1908. 

45.  Buchanan :  Mai.  Fev.  and  Mai.  Parasites  in  India,  Calcutta,  1903. 

46.  Cited  by  Buchanan  (45). 

47.  Tsuzuki :  Malaria,  vol.  i. 

48.  Ziemann :  Mense's  Handbuch  der  Tropenkrankheiten,  Leipzig,  1906. 

49.  Medizinal   Berichte  iiber   die   Deutschen   Schutzgebiete,    1904-05   and 

1905-06. 

50.  Thiroux  et  d'Anpreville,  Le  Paludisme  au  Senegal,  Paris,  1908. 

51.  Medizinal    Berichte   iiber   die   Deutschen    Schutzgebiete,    1904-05. 

52.  Ibid.    1905-06. 

53.  Otto :  Deut.  Med.  Woch.,  1902,  No.  4. 

54.  Brault :  Janus,  Nov.  15,  1903. 

55.  Coste:  Rev.  in  La  Presse  Med.,  Sept.  12,  1906. 

56.  Wellman :  Jour.  Am.  Med.  Assoc,  45,  1736. 

57.  Reports  to  the  Malarial  Committee,  5th  Series,  London,  1901. 

58.  F.  Plehn:  Deut.  Med.  Woch.,  1901,  p.  838. 

59.  Manson:  Tropical  Diseases,  London,  1903. 

60.  Johnson :  Jour.  Trop.  Med.,  Dec.  15,  1900. 

61.  F.  Plehn:  Deut.  Med.  Woch.,  1895,  25-27. 

62.  A.  Plehn:  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  iii,  4. 

63.  Jour.  Am.  Med.  Assoc,  48,  1195. 

64.  Masterman :  Brit.  Med.  Jour.,  Feb.  10,  1906. 

65.  Drake :  Principal  Diseases  of  the  Valley  of  North  America,  Cincin- 

nati, 1850. 

66.  Davidson,  Hygiene  and  Diseases  of  Warm  Climates,  Edinb.,  1893. 

67.  Cited  by  Marchiafava  and  Bignami  (22). 

68.  Atti  della  Societa  per  gli  Studi  della  Malaria,  Rome,  1907. 

69.  Koch:  Deut.  Med.  Woch.,  Feb.  1,  1900. 

70.  Craig:  Estivo-autumnal  Malaria,  New  York,  1901. 

71.  Lind:  Diseases  Incidental  to  Europeans  in  Hot  Climates,  Phila.,  181 1. 

72.  Watson:  Practice  of  Physic,  Phila.,  1854. 

73.  Sternberg:  Malaria  and  Malarial  Diseases,  New  York,  1884. 

74.  La  Roche :  Pneumonia  and  Malaria,  Phila.,  1854. 

75.  Maurel :  Maladie  Paludeennes  a  la  Guyane,  Paris.  1883. 

76.  Med.  and  Surg.  History  of  the  War  of  the  Rebellion,  iii,  med.  vol. 

77.  Smith :  Brit.  Med.  Jour.,  Dec.  17,  1898. 

78.  Koch:  Deut.  Med.  Woch.,  Dec.  6,  1900. 

79.  Cited  by  Ziemann  (48). 


390  THE    STUDY   OF  MALARIA 

80.  Celli :  La  Malaria  Secondo  le  Nuove  Ricerche,  Rome. 

81.  Erni :  Arch,  f iir  Schiff s.-  u.  Trop.  Hyg.,  June,  1899. 

82.  Atti  della  Societa  per  gli  Studi  della  Malaria,  Rome,  1906. 

83.  Ibid.,  1908. 

84.  Ibid.,  1904. 

85.  Jour.  Am.  Med.  Assoc,  51,  916. 

86.  Cited  by  Laveran  (1). 

87.  Strachan:  Brit.  Med.  Jour.,  March  18,  1905. 

88.  Ross :  Brit.  Med.  Jour.,  Sept.  14,  1901. 

89.  Panse :  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  1902,  No.  12. 

90.  Cited  by  Ruge   (158). 

91.  Craig :  Yale  Med.  Jour.,  June,  1907. 

92.  Schellong:  Die  Malariakrankheiten,  Berlin,  1890. 

93.  Hadjimichalis  and  Cardamatis,  Ann.  Trop.  Med.  and  Par.,  ii,  2. 

94.  Report  to  the  Malarial  Committee,  6th  Series,  London,  1902. 

95.  Russell:  Malaria  and  Injuries  of  the  Spleen,  Calcutta,  1880. 

96.  Cited  by  Mannaberg  (141). 

97.  Felkin :  Edinb.  Med.  Jour.,  June,  1889. 

98.  Thayer:  Lectures  on  the  Malarial  Fevers,  New  York,  1901. 

99.  A.   Plehn:   Die  Malaria  der  Afrikanischen  Negerbevolkerung,  Jena, 

1902. 

100.  Pezopoulos  and  Cardamatis :  Arch,  de  Med.  des  Enfants,  Jan.,  1907. 

101.  Cited  by  Manson  (59). 

102.  Winslow :  Boston  Med.  and  Surg.  Jour.,  May  27,  1897. 

103.  Peters :  Johns  Hopkins  Hosp.  Bull.,  June,  1902. 

104.  Moffatt :  Brit.  Med.  Jour.,  May  4,  1907. 

105.  Cited  by  Crespin  (144). 

106.  Hitte :  These  de  Montpellier,  1902. 

107.  Holt:  Diseases  of  Infancy  and  Childhood,  New  York,  1908. 

108.  Economous :  Bull,  de  la  Soc.  d'Obstet,  x,  70,  1907. 

109.  Bell:  Jour.  Am.  Med.  Assoc,  51,  1993. 
no.  Cited  by  Thayer  and  Hewetson  (29). 
in.  Jeffries:  Med.  Record,  57,  654. 

112.  Daniels:  Brit.  Med.  Jour.,  Jan.  26,  1901. 

113.  Stephens  and  Christophers:  Thomp.  Yates  Lab.  Rep.,  v.  i. 

114.  Cited  by  Howard   (122). 

115.  Cited  by  Galli-Vallerio  et  de  Jongh  (124). 

116.  Banks :  The  Philippine  Journal  of  Science,  Dec,  1907. 

117.  Cited  by  Austin,  The  Practitioner,  March,  1901. 

118.  Stephens  and  Christophers:  Practical  Study  of  Malaria,  London,  1904. 

119.  Giles:  The  Gnats  or  Mosquitoes,  London,  1902. 

120.  Coquillett :  Class,  of  the  Mosq.  of  North  and  Middle  America,  Wash., 

1906. 

121.  Sambon :  Brit.  Med.  Jour.,  Sept.  24,  1008. 

122.  Howard:  Mosquitoes,  New  York,  1902. 

123.  Nuttall:  Brit.  Med.  Jour.,  Sept.  14,  1901. 

124.  Galli-Vallerio  et  de  Jongh :  Manuel  pour  la  Lutte,  etc.,  Paris,  1906. 

125.  Pressat :  Le  Paludisme  et  les  Moustiques,  Paris,  1905. 

126.  Mitchell:  Mosquito  Life,  1907. 

127.  Eyesell :  Arch,  fur  Schiffs.-  u.  Trop,  Hyg.,  xi,  6. 

128.  Woldert:  Jour.  Am.  Med.  Assoc,  50,  1249. 

129.  Cited  by  Stephens  and  Christophers  (118). 

130.  Ewing:  Jour.  Exp.  Med.,  March  25,  1901. 

131.  Cited  by  Mannaberg  (404)- 

132.  Cited  by  Ewing  (130). 

133.  Cited  by  Schaudinn  (134)- 

134.  Schaudinn:  Arbeiten  aus  den  Kaiserl.  Ges.  Amt,  19,  2. 

135.  Maurer:  Centralbl.  fur  Bakt.,  Parasit.,  etc.,  Nov.  5,  1902. 

136.  Bluml  and  Metz :  Arch,  fur  Schiffs.-  und  Trop.  Hyg.,  xii,  249. 

137.  Craig:  International  Clinics,  17th  Series,  in. 

138.  Cited  by  Craig  (70). 


REFERENCES  39I 

139.  Cited  by  Thayer  (98). 

140.  Ford :  Jour.  Am.  Med.  Assoc,  48,  133 ;  Med.  Record,  66,  1001. 

141.  Mannaberg:  Malarial  Diseases,  Phila.,  1905. 

142.  Rosenau  et  ah:    Exp.   Stud,   in  Yellow   Fever  and  Malaria,   Wask., 

1905. 

143.  Koch :  Deut.  Med.  Woch.,  May  3,  1900. 

144.  Crespin :  Precis  du  Paludisme,  Paris,  1905. 

145.  Bell:  The  Lancet,  Aug.  24,  1900. 

146.  Santos  :  L'Influence  de  l'lmpaludisme,  etc.,  Rio  de  Janeiro,  1888. 

147.  Atti  della  Societa  per  gli  Studi  della  Malaria,  Rome,  1902. 

148.  Thornhill:  Indian  Med.  Gaz.,  March,  1898. 

149.  Cited  by  Burot  et  Legrand  (212). 

150.  Atti  della  Societa  per  gli  Studi  della  Malaria,  Rome,  1901. 

151.  Billet:  Revue  de  Medicine,  Dec,  1902. 

152.  Sims :  Jour.  Trop.  Med.,  Jan.   15,  1902. 

153.  Rees :  Brit.  Med.  Jour.,  Feb.  10,  1900. 

154.  Satterlee:  New  York  Med.  Jour.,  April  11,  1908. 

155.  Hall :  Denver  Med.  Times,  April  1908. 

156.  Neer:  Jour.  Am.  Med.  Assoc,  50,  1890. 

157.  Homem :  Pernicious  Fever,  Detroit,  1904. 

158.  Ruge :  Einfiihrung  in  das  Studium  der  Malariakrankheiten,  Jena,  1906. 

159.  Cited  by  Le  Dantec  (226). 

160.  Wurtz  and  Thiroux :  Diag.  et  Sem.  des  Malad.  Trop.,  Paris,  1905. 

161.  Roux :  Maladies  des  Pays  Chauds,  Paris,  1886. 

162.  Marchiafava  and  Bignami :  Summer  and  Autumn,  Mai.  Fever,  London, 

1894. 

163.  Van  der  Scheer :  Virchow's  Archiv.,  139,  1. 

164.  Craig:  Osier's  Modern  Medicine,  Phila.,  1907,  vol.  i. 

165.  Crespin :  La  Caducee,  May  2,  1903. 

166.  French:  New  York  Med.  Jour.,  May  23,  1896. 

167.  Hunt:  New  York  Post-Graduate,  Nov.,  1906. 

168.  Cited  by  Sutherland:  Memphis  Med.  Monthly,  July,  1905. 

169.  Ficucci:  Rev.  in  Med.  Record,  71,  870. 

170.  Fenner :  N.  O.  Med.  and  Surg.  Jour.,  Dec,  1903. 

171.  A.  Plehn :  Beitr.  zur  kennt.  der  Trop.  Malaria,  Berlin,  1896. 

172.  Koch:  Arbeiten  aus  den  Kaiserl.  Gesundh.  Amt,  14,  2. 

173.  Cited  by  Rho :  La  Malaria,  Turin,  1896. 

174.  Barker :  Study  of  Some  Fatal  Cases  of  Malaria,  Baltimore,  1895. 

175.  Zeri :  II  Policlinico,  April,  1904. 

176.  Bloomberg  and  Coffin :  Am.  Med.,  Nov.  25,  1905. 

177.  Ewing:  Am.  Jour.  Med.  Sci.,  Oct.,  1901. 

178.  Kelsch  and  Kiener :  Maladies  des  Pays  Chauds,  Paris,  1889. 

179.  Cited  by  Ewing  (181). 

180.  Ford :  Med.  Record,  April  5,  1902. 

181.  Ewing:  Jour.  Exp.  Med.,  Feb.  5,  1902. 

182.  Mercier :  Le  Paludisme  Observe  sous  les  Tropiques,  Paris,  1905. 

183.  Hertz :  Ziemssen's  Cyclopedia,  New  York,  1875,  vol.  ii. 

184.  Hanley:  Jour.  Trop.  Med.,  1899,  p.  85. 

185.  Cited  by  F.  Plehn   (208). 

186.  Curry:  Jour.  Am.  Med.  Assoc,  38,  1130. 

187.  Doerring:  Deut.  Med.  Woch.,  Nov.  14,  1895. 

188.  Reynolds:  Jour.  Trop.  Med.,  Jan.,  1899. 

189.  Goltman  and  Krauss :  Memphis  Lancet,  Dec,  1898. 

190.  Personal  Communication. 

191.  Cited  by  F.  Plehn  (5). 

192.  Lewis:  N.  C.  Med.  Jour.,  March  5,  1899. 

193.  Francez:  N.  O.  Med.  and  Surg.  Jour.,  July,  1902. 

194.  Minos :  Med.  News,  Nov.  24,  1883. 

195.  McKay:  Am.  Pract.  and  News,  June  1,  1902. 

196.  Tyson:  Med.  News,  May  12,  1883. 

197.  Daniels:    Laboratory    Studies    in    Tropical    Medicine,    Phila.,    1903. 


392  THE  STUDY   OF   MALARIA 

198.  Cardamatis :  La  Grece  Medicale,  April,  1900. 

199.  Krauss :  Memphis  Med.  Monthly,  April,  1902. 

200.  Deaderick:  Memphis  Med.  Monthly,  Aug.,  1907. 

201.  Mense :  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  June,  1899. 

202.  Lipari:  II  Morgagni,  Sept.,  1889. 

203.  Cited  by  Scheube  (27). 

204.  Cited  by  Burns  (235). 

205.  Tomaselli :  La  Intossicazione  Chinica,  etc.,  Catani,  1897. 

206.  Cardamatis :  La  Fievre  Bilieuse  Hemoglobinurique,  Paris,  1902. 

207.  Foustanos :  La  Grece  Medicale,  April,  1900. 

208.  F.  Plehn :  Arch,  fiir  Schiffs.-  u.  Trop.  Hyg.,  iii,  6. 

209.  Crosse :  Brit.  Med.  Jour.,  Oct.  8,  1898. 

210.  Banks :  Jour.  Trop.  Med.,  Dec.  15,  1900. 

211.  F.  Plehn:  Tropenhygiene,  Jena,  1906. 

212.  Burot  and  Legrand :   Maladies   du  Soldat  aux   Pays   Chauds,   Paris, 

1897. 

213.  Vedy:  La  Fievre  Bilieuse  Hemoglobinurique,  etc.,  Brussels,  1907. 

214.  McElroy:  Memphis  Med.  Monthly,  May  and  June,  1905. 

215.  Brem:  Jour.  Am.  Med.  Assoc,  Dec.  8-15,  1906. 

216.  Howard :  Jour.  Trop.  Med.,  March  1,  1907. 

217.  Bassett-Smith :  Jour.  Trop.  Med.,  1907,  x,  69. 

218.  Hughes :  Jour.  Trop.  Med.,  June,  1899. 

219.  Manson:  Brit.  Med.  Jour.,  May  16,  1903. 

220.  Parker:  Brit.  Med.  Jour.,  Sept.  9,  1899. 

221.  Mowbray:  The  Lancet,  Aug.  26,  1905. 

222.  Schlayer:  Deut.  Med.  Woch.,  July  10,  1902. 

223.  Kleine:  Brit.  Med.  Jour.,  Sept.  14,  1901. 

224.  Koch:  Jour.  Trop.  Med.,  July  15,  1899. 

225.  Burot  et  Legrand:  Therapeutique  du  Paludisme,  Paris,  1897. 

226.  Le  Dantec:  Pathologie  Exotique,  Paris,  1905. 

227.  Cited  by  Kelsch  and  Kiener  (178). 

228.  Dryepondt  and  Vancampenhout :  Jour  de  Med.  de  Bruxelles,  1899,  9. 

229.  Bertrand:  Ann.  Soc.  Med.-Chi.  d'Anvers,  Nov.  and  Dec,  1899. 

230.  Mould:  Brit.  Med.  Jour.,  Sept.  9,  1899. 

231.  Haig:  The  Lancet,  April  2,  1898. 

232.  Cited  by  Mense:  Archiv.  fiir  Schiffs.-  u.  Trop.  Hyg.,  iii,  2. 

233.  Cited  by  Marchiafava  and  Bignami  (162). 

234.  Cited  by  A.  Plehn  (62). 

235.  Burns:  Jour.  Am.  Med.  Assoc,  Nov.  17,  10,  1900. 

236.  Crosse :  The  Lancet,  Jan.  6,  1900. 

237.  Thin:  Brit.  Med.  Jour.,  Sept.  I,  1900. 

238.  Ketchen :  Brit.  Med.  Jour.,  Nov.  10,  1906. 

239.  Ruge:  Deut.  Med.  Woch.,  July  10,  1902. 

240.  Woldert :  New  York  Med.  Jour.,  Feb.  23,  1895. 

241.  Hartsock:  New  York  Med.  Jour.,  Sept.  13,  1902. 

242.  Broden:  Trav.  du  Lab.  Med.  de  Leopoldville,  Brussels,  1906. 

243.  Cited  by  Cardamatis  (244). 

244.  Cardamatis:  Progres  Medical,  1902,  Nos.  37~40- 

245.  Virchow's  Jahresbericht,  bd.,  I,  1907. 

246.  Grattan :  Jour.  Royal  Army  Med.  Corps,  1907,  ix,  3,  p.  237. 

247.  Kulz :  Arch,  fiir  Schiffs.-  u.  Trop.  Hyg.,  xii,  242. 

248.  Smith  and  Kilbourne,  Texas  or  Southern  Cattle  Fever,  Washington, 

1893- 

249.  Orme :  Jour.  Trop.  Med.,  Feb.  1,  1908. 

250.  Cited  by  Crosse  (4). 

251.  Cited  by  Brem  (215). 

252.  Cited  by  Vedy  (213).  tt 

253.  Cited  by  Koch :  Arch,  fiir  Schiffs.-  u.  Trop.  Hyg.,  June,  1899. 

254.  Ellenbeck-Hilden,  Beobachtungen  iiber  Malaria,  Berlin    1005.  _ 

255.  Legrain:  Introd.  a  l'Etude  des  Fievres  des  Pays  Chauds,  Paris,  1899- 

256.  Grail:  Pathologie  Exotique,  Paris,  1900. 


REFERENCES  393 

257.  Rossoni :  II  Morgagni,  Jan.,  1899. 

258.  Heal :  Jour.  Trop.  Med.,  Feb.  15,  1899. 

259.  Stalkarrt:  Brit.  Med.  Jour.,  Sept.  9,  1899. 

260.  Hopkins :  Dublin  Jour,  of  Med.  Sci.,  June,  1903. 

261.  Cited  by  Crosse  (236). 

262.  Rankin :  Brit.  Med.  Jour.,  Sept.  1,  1900. 

263.  Moffatt :  Brit.  Med.  Jour.,  Jan.  25,  1902. 

264.  McElroy :  Jour.  Am.  Med.  Assoc,  41,  605. 

265.  Dubose :  Jour.  Am.  Med.  Assoc.,  March  11,  1899. 

266.  Hearsey,  Brit.  Med.  Jour.,  Jan.  26,  1901. 

267.  Shropshire:  Jour.  Am.  Med.  Assoc,  41,  600. 

268.  Murri :  Deut.  Med.  Woch.,  Feb.  20-27,  1896. 

269.  Marsden :  Brit.  Med.  Jour.,  Sept.  1,  1900. 

270.  Boxer:  Brit.  Med.  Jour.,  May  7,  1904. 

271.  Cited  by  Koch  (253). 

272.  Transactions  of  the  Epidemologic  Society,  1892-93. 

273.  Cited  by  Stalkarrt   (259). 

274.  Yersin:  Compt.  Rend.  Soc  Biol.,  Paris,  1895,  ii,  447. 

275.  Breaudat :  Arch,  de  Med.  Nav.,  1896,  457. 

276.  Collett:  The  Lancet,  Dec.  28,  1904. 

277.  Wasserman:  Immune  Sera,  New  York,  1904. 

278.  Deaderick :  Jour.  Am.  Med.  Assoc,  June  1,  1907. 

279.  Christophers  and  Bentley:  Blackwater  Fever,  Simla,  1908. 

280.  Billings :  Johns  Hopkins  Hosp.  Bull.,  Oct.,  1894. 

281.  Krauss:  Jour.  Am.  Med.  Assoc,  43,  1202. 

282.  Thayer :  Am.  Jour.  Med.  Sci.,  Nov.-Dec,  1898. 

283.  Anders :  Jour.  Am.  Med.  Assoc,  June  15,  1895. 

284.  Atkinson :  Am.  Jour.  Med.  Sci.,  July,  1884. 

285.  Cited  by  Wurtz  and  Thiroux  (160). 

286.  Brown :  Jour.  Ark.  and  Med.  Soc,  Dec.  15,  1907. 

287.  Cardamatis :  Bull,  de  la  Soc.  de  Med.  de  Gand.,  Feb.,  1901. 

288.  Morris :  S.  W.  Med.  Record,  July,  1899. 

289.  Cited  by  Roux  (161). 

290.  Cited  by  Hertz  (183). 

291.  Colin:  Traite  des  Fievres  Intermittentes,  Paris,  1870. 

292.  Kanellis  and  Cardamatis :  Le  Progres  Medical,  May  19,  1900. 

293.  Craig:  Med.  Record,  Feb.  15,  1902. 

294.  Gillot:  Semaine  Med.,  Sept.  13,  1905. 

295.  Wolf:  New  England  Med.  Monthly,  Nov.,  1903. 

296.  Chamberlain:  Bost  Med.  and  Surg.  Jour.,  Jan.  11,  1905. 

297.  Craig:  Am.  Med.,  Oct.  29,  1904. 

298.  Ross  and  Daniels :  Jour.  Trop.  Med.,  Feb.  15,  1902. 

299.  Marchoux:  Le  Caducee,  Aug.  20,  1904. 

300.  Fiemsa  and  Schaumann :  Studien  iiber  Chinin,  Leipzig,  1907. 

301.  Williams :  Jour.  Trop.  Med.,  Dec  15,  1900. 

302.  Mackie:  The  Lancet,  Dec.  6,  1898. 

303.  Christophers  and  Bentley:  Indian  Med.  Gazette,  March,  1908. 

304.  Cited  by  Legrain  (255). 

305.  Cohen:  Am.  Jour.  Med.  Sci.,  136,  344. 

306.  Rist  and  Boudet :  La  Presse  Medicale,  Dec.  4,  1907. 

307.  Craig:  Med.  Record,  Feb.  15,  1902. 

308.  Ziemann :  Deut.  Med.  Woch.,  June  21,  1900. 

309.  Wellman:  Proc  Am.  Soc.  Trop.  Med.,  1905. 

310.  Annett,  Dutton  and  Elliott :  Brit.  Med.  Jour.,  Sept.  14,  1901. 

311.  Triantaphyllides :  La  Grece  Med.,  v.  11-12. 

312.  Raymond :  These  de  Montpelier.  1806. 

313.  Jenness:  U.  S.  Naval  Med.  Bull.,  Jan.,  1908. 

314.  Hemmeter:  Am.  Med.,  Nov.  14.  1903. 

315.  Cohen  and  Rosenberger,  Am.  Jour.  Med.  Sci.,  August,  1904. 

316.  Trans,  of  Assoc,  of  Am.  Physicians,  1902. 

317.  Palmer :  The  Lancet,  Dec.  24,  1892. 


394  THE   STUDY   OF   MALARIA 

318.  Brault:  Maladies  des  Pays  Chauds,  Paris,  1900. 

319.  Messerer :  These  de  Paris,  1886. 

320.  Goltman :  Memphis  Med.  Monthly,  Nov.,  1905. 

321.  Moore:  Am.  Med.,  Dec.  28,  1901. 

322.  Duprey:  Jour.  Trop.  Med.,  Sept.  16,  1907. 

323.  Cited  by  Behrmann :  Berlin  Klin.  Woch.,  Aug.  24,  1885. 

324.  Goth :  Zeitschr.  fur  Geb.  u.  Gynak.,  vii,  1,  1881. 

325.  Bonfils :  Paludisme  et  Puerperalite,  Paris,  1885. 

326.  Williams :  A  Text-book  of  Obstetrics,  New  York,  1903. 

327.  Glogner :  Virchow's  Archiv.,  1895,  :4°>  P-  481- 

328.  Price:  Am.  Med.,  June  3,  1905. 

329.  DaCosta :  International  Clinics,  Series  1891,  iii. 

330.  Fornaca :  II  Policlinico,  1907,  51. 

331.  Torti :  Riforma  Med.,  1891,  xii. 

332.  Spiller:  Am.  Jour.  Med.  Sci.,  Dec,  1900. 

333.  Ziemann :  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  xii,  501. 

334.  Winfield:  New  York  Med.  Jour.,  Aug.  2,  1902. 

335.  Bastianelli  and  Bignami :  Bull.  d.  Soc.  Lancis,  Rome,  1890,  lx,  x. 

336.  Deaderick :  Southern  Med.  Jour.,  Oct.,  1908. 

337.  Anders :  Phila.  Hosp.  Reports,  iv,  1895. 

338.  Loffler :  Deut.  Med.  Woch.,  1901,  No.  42. 

339.  Valenti :  II  Policlinico,  xiv,  48,  1907. 

340.  Lioubenetzky :  Semaine,  Med.,  1908,  18. 

341.  Mallory  and  Wright :  Pathological  Technique,  Phila.,  1904. 

342.  Cabot:  Am.  Med.,  Dec.  20,  1902;  Bost.  Med.  and  Surg.  Jour.,  March 

24,  1904. 

343.  Fornario :  Deut  Med.  Woch.,  Jan.  22,  1903. 

344.  McElroy:  Memphis  Med.  Monthly,  Nov.,  1902. 

345.  A.  Plehn:  Weiteres  iiber  Malaria,  etc.,  Jena,  1901. 

346.  Delaney:  Brit.  Med.  Jour.,  March  28,  1903. 

347.  Vincent:  Ann.  de  l'lnstitut.  Pasteur,  Dec.  25,  1897. 

348.  Ross :  The  Lancet,  Nov.  17,  1906. 

349.  Ross :  The  Lancet,  Sept.  28,  1907. 

350.  Hagen :  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  iv,  iii. 

351.  Jour.  Trop.  Med.,  vol.  xi. 

352.  Haw:  Jour.  Trop.  Med.,  Oct.  16,  1899. 

353.  Laveran :  Bull,  de  TAcad.  de  Med.,  lxix,  32. 

354.  Gorgas :  Jour.  Am.  Med.  Assoc,  46,  1417. 

355.  Annual  Reports,  U.  S.  P.  H.  and  M.  H.  S.,  1905-07. 

356.  Medizinal  Berichte  iiber  die  Deutsch,  Schutzgeb.,  1903-06. 

357.  Parry:  Am.  Jour.  Med.  Sci.,  vii,  339. 

359.  Cited  by  Cardamatis  (287). 

360.  Cited  by  Wood :  Practical  Medicine,  Phila.,  1847. 

361.  Charity  Hosp.  Reports,  New  Orleans,  1906-07. 

362.  Cited  by  Cardamatis  (363). 

363.  Cardamatis :  Bull,  de  la  Soc.  de  Med.  de  Gand.,  Nov.,  1900. 

364.  Cited  by  Cardamatis   (365). 

365.  Cardamatis :  Bull,  de  la  Soc.  de  Med.  de  Gand.,  Oct.,  1900. 

366.  Jenkins :  Trans.  Ark.  Med.  Soc,  1904,  203. 

367.  Cited  by  Sambon  (9). 

368.  Michel:  N.  O.  Jour,  of  Med.,  1869. 

369.  Malone :  Trans.  Ark.  Med.  Soc,  1880,  v,  74. 

370.  Coste :  Rev.  in  La  Presse  Med.,  Sept.  12,  1906. 

371.  Steggall :  Med.  Record,  56,  259. 

372.  Austin :  Brit.  Med.  Jour.,  Feb.  10,  1900. 

373.  Cited  by  Cardamatis,  F.  B. :  Hemoglobinurique,  Syra,  1901. 

374.  McDaniel:  Med.  News,  Nov.  24,  1883. 

375.  Henric :  Arch,  de  Med.  Nav.,  May,  1898. 

376.  Kohlstock:  Deut.  Med.  Woch.,  Nov.  14,  i895- 

377.  Ensor:  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  108. 

378.  Cited  by  F.  Plehn  (6). 


REFERENCES  395 

379.  Cited  by  Hopkins  (260). 

380.  Cited  by  Prentice :  Brit.  Med.  Jour.,  Sept.  24,  1898. 

381.  Dempwolff:  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  June,  1899. 

382.  Cited  by  Hare:  Ther.  Gaz.,  July  15,  1892. 

383.  Cited  by  Lewis   (192). 

384.  Forde:  Jour.  Trop.  Med.,  Feb.  1,  1908. 

385.  Cardamatis :  Fievre  Bilieuse  Hemoglobinurique,  Syra,  1901. 

386.  Prout :  Brit.  Med.  Jour.,  Nov.  9,  1907. 

387.  Jacobs :  New  York  Med.  Jour.,  Oct.  12,  1907. 

388.  DeCruz :  Indian  Med.  Gaz.,  Nov.,  1907. 

389.  DeBlasi :  Gazet.  degli  Osped.,  April  26,  1903. 

390.  Orme :  Jour.  Trop.  Med.,  xi,  38. 

391.  Thompstone :  Jour.  Trop.  Med.,  xi,  14. 

392.  Ross :  Mosquito  Brigades,  New  York,  1902. 

393.  Rosenau :  Disinfection  Against  Mosquitoes,  etc.,  Washington,  1901. 

394.  Cited  by  Smart  (76). 

395.  Babes :  Munch.  Med.  Woch.,  April  4,  1905. 

396.  Duncan :  Brit.  Med.  Jour.,  Sept.  1,  1900. 

397.  Annual  Report  U.  S.  P.  H.  and  M.  H.  S.,  Washington,  1906. 

398.  Sambon  and  Low :  Brit.  Med.  Jour.,  Dec.  8,  1900. 

399.  Busck:  Jour.  Trop.  Med.,  xi,  252. 

400.  Kleine:  Zeitschr.  fur  Hyg.  Infek.,  38,  1907. 

401.  Cited  by  Giemsa  and  Schaumann  (300). 

402.  Schmitz :  Arch,  fur  Exp.  Path.  u.  Pharm.,  1907. 

403.  Craig:  Am.  Med.,  April  and  May,  1906. 

404.  Mannaberg:  Die  Malaria  Parasiten,  Vienna,  1893. 

405.  Gudden :  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  1905,  500. 

406.  A.  Plehn :  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  ii,  4. 

407.  Grenier :  Indian  Med.  Gaz.,  Feb.,  1898. 

408.  Quill :  Rev.  in  Med.  News,  Dec.  5,  1903. 

409.  Goodman :  Med.  Record,  70,  865. 

410.  Cited  by  Tomaselli  (205). 

411.  Moore :  The  Lancet,  1863,  660. 

412.  Cited  by  Mauviez :  Le  Paludisme  a  Diego-Suarez,  Paris,  1905. 

413.  Bartholow:  Materia  Medica,  New  York,  1894. 

414.  Cited  by  McCampbell   (415). 

415.  McCampbell :  Jour.  Am.  Med.  Assoc,  48,  920. 

416.  Bliimchen :  Deut.  Med.  Woch.,  1901,  No.  17. 

417.  Manson :  Lectures  on  Tropical  Diseases,  Chicago,  1905. 

418.  Cited  by  McElroy  (214). 

419.  Gros :  Bull,  de  la  Soc.  de  Med.  de  Gand,  Oct.,  1900. 

420.  Shoemaker :  Med.  Record,  Oct.  29,  1904. 

421.  Cited  by  Vanderhoof :  Jour.  Am.  Med.  Assoc,  48,  1333. 

422.  Bacelli :  Gaz.  degli.  Osped.,  Feb.,  1890 ;  Riform.  Med.,  1890,  6. 

423.  Guiterrez :  Rev.  in  Jour.  Am.  Med.  Assoc,  Nov.  22,  1902. 

424.  Fleury:  Jour.  Am.  Med.  Assoc,  Dec.  24,  1904. 

425.  Holmes :  Medical  Essays,  Boston,  1895. 

426.  Demarchi :  Policlinico,  1906,  xiii,  6. 

427.  Brachio :  Indian  Med.  Gaz.,  March,  1908. 

428.  Bell :  The  Military  Surgeon,  August,  1907. 

429.  Goltman:  Memphis  Med.  Monthly,  Nov.,  1905. 

430.  Guttman  and  Ehrlich :  Berlin  Klin.  Woch.,  1891,  39. 

431.  Wood:  Med.  News,  March  4,  1905. 

432.  De  Blasi :  Gaz.  degli  Ospedali,  March  23,  1902. 

433.  Thayer :  Bull.  Johns  Hopkins  Hosp.,  May,  1892. 

434.  Moore  and  Allison :  Med.  News,  Dec.  6,  1902. 

435.  Grosch :  Med.  Klinik.,  1907,  20. 

436.  Wiener :  Klin.  Woch.,  June  4,  1908. 

437.  Vassal :  Le  Caduccee,  ninth  year,  9. 

438.  Duncan:  Jour.  Trop.  Med.,  Oct.  16,  1899. 

439.  Carpenter :  Med.  Record,  70,  165. 


396  THE   STUDY   OF   MALARIA 

440.  Quennec:  Arch,  fur  Schiffs.-  u.  Trop.  Hyg.,  iii,  2. 

441.  Vincent:  Compt.  Rend.  Soc.  Biol.,  Dec.  15,  1905. 

442.  Polli :  Brit.  Med.  Jour.,  Nov.  16,  1867. 

443.  O'Sullivan-Beare :  The  Lancet,  Feb.  1,  1902. 

444.  Werner:  Deut.  Med.  Woch.,  1902,  42. 

445.  Cited  by   Werner:   Die   Nieren   beim   Schwarzwasserfieber,   Leipzig, 

1907. 

446.  Kiilz :  Arch,  f iir  Schiffs.-  u.  Trop.  Hyg.,  xi,  508. 

447.  Cited  by  Ed.  Jour.  Am.  Med.  Assoc,  June  24,  1905. 

448.  Below:  Berl.  Klin.  Woch.,  Nov.  15,  i897- 

449.  McKay:  Glasgow  Med.  Jour.,  March,  1908. 


INDEX 


Abdominal  forms,  212 

Abortion,  242 

Abscess  of  liver,  diagnosis,  284 

of  spleen,  240 
Absorption  of  quinine,  335 
Action  of  quinine  on  parasites,  341 
Acute  malaria,  184 
Administration  of  quinine,  357 
Adult  mosquitoes,  81 
Aedeomyia,  100 
Aedes,  93 
Age,  55,  253 

and  hemoglobinuric  fever,  155 

and  immunity,  53 

and  pernicious  malaria,  141 
Agglutinin,  199 
Albuminuria,  201 
Algid  form,  212 
Alkaloids  of  cinchona,  343 
Altitude,  45 

and  hemoglobinuric  fever,  158 

and  mosquitoes,  104 
Amaurosis,  210 
Amblyopia,  diagnosis,  289 
Anemia,  pathogenesis,  140 
Anopheles,  88 

breeding  places  of,  75 

crucians,  description,  86 

maculipennis,  description,  84 

mosquitoes,  74 

punctipennis,  description,  85 
Anophelinae,  87 
Anopheline  larvae,  77 

ova,  76 
Apoplectic  form,  208 
Apparent  death,  207 
Appendicitis,  215 
Ardent  form,  210 
Ataxic  form,  210 


Bacillus  malariae,  20 
Banti's  disease,  diagnosis,  287 
Beans  and  hemoglobinuria,  168 
Bilious  form,  215 

remittent  fever,   and    hemoglobin- 
uria, 27 
diagnosis,  291 
Biology  of  parasites,  113 
Biting  of  mosquitoes,  105 
Blackwater  fever.     See  Hemoglobinuric 

fever. 
Blood,  195,  216,  223 

complications,  236 

examination,  258 
Bone-marrow,  pathology,  177,  180,  183 
Brain,  pathology,  177,  183 
Breeding  mosquitoes,  109 

places,  75 
Bulbar  symptoms,  208 

Cachexia,  237 

productive  of  immunity,  54 

treatment,  369 
Cacomyia,  10 1 
Cancer,  complication,  251 
Cardialgic  form,  214 
Cellia,  89 

Cerebellar  symptoms,  208 
Cerebrospinal  forms,  204 
Change  of  residence,  53,  60 

and  hemoglobinuric  fever,  158 
and  pernicious  malaria,  143 

of  type,  139,  188 
Children,  malaria  in,  55,  56,  253 

pernicious  malaria  in,  141 

treatment,  371 
Chill,  description,  184 
Choice  of  preparation,  356 
Choleraic  form,  214 

397 


39« 


INDEX 


Chronic  malaria,  228 

treatment,  368 
Cinchona,  history,  28 
Circulatory  system,  complications,  232 

symptoms,  195 
Civilization,  61 
Classification  of  mosquitoes,  86 

of  parasites,  112 

of  pernicious  malaria,  203 
Clearing  of  land,  48 
Climate,  38 
Clinical  history,  184 
Colon  bacillus,  252 
Colors  and  mosquitoes,  106 
Comatose  malaria,  204 
Complications,  232 

of  hemoglobinuric  fever,  226 

treatment,  372 
Congenital  immunity,  54 

malaria,  64 
Contra-indications  to  quinine,  355 
Convulsive  form,  209 
Coquillettidia,  100 
Crescents,  231 

pyrogenic  properties,  147 
Culex,  98 
Culicella,  97 
Culicinae,  87,  90 
Culiseta,  98 

Cultivation  experiments,  129 
Cycles  of  the  parasites,  114 
Cycloleppteron,  89 

Deinocerites,  101 
Deinoceritinse,  87,  101 
Dendromyia,  103 
Destruction  of  mosquitoes,  305 

of  parasites,  315 
Diabetes,  complication,  251 
Diagnosis,  256 

differential,  284 

of  hemoglobinuric  fever,  289 

of  pernicious  malaria,  287 
Diaphoretic  form,  214 
Differential  diagnosis,  284 
Disappearance  of  malaria,  73 
Dissection  of  mosquitoes,  no 
Dissemination  by  mosquitoes,  69 
Dosage  of  quinine,  365 
Drinking-water,  62 


Duration  of  larval  stage,  79 
Dysenteric  form,  214 

Ear  complications,  248 
Earthquakes,  46 
Eclamptic  form,  209 
Education  and  prophylaxis,  327 
Eggs  of  mosquitoes,  76,  107 
Elimination  of  quinine,  335 
Endemic  index,  56 
Endocarditis,  diagnosis,  284 
Endogenous  cycle,  114 
Epidemics,  63 

of  hemoglobinuric  fever,  37 
Error,  sources  of,  268 
Estivo-autumnal    infection,    symptoms^ 
190 

parasites,  119 

differentiation,  121 
Etiology,  38 

of  hemoglobinuric  fever,  153 

of  pernicious  malaria,  140 
Europeans  and  hemoglobinuric  fever,  29 
Examination  of  blood,  258 
Exclusion  of  mosquitoes,  322 
Exflagellation,  117 
Exogenous  cycle,  123 
Exposure,  60 

to  wind,  49 
External  etiologic  influences,  151 
Eye  complications,  248 

Family    predisposition    and    hemoglo- 
binuria, 156 

Feeding  of  mosquitoes,  70,  no 

Females,  susceptibility  of,  54 

Fertilization  of  mosquitoes,  70,  107 

Fish  and  prophylaxis,  311 

Flagella,  117,  268 

Flight  of  mosquitoes,  105 

Food  in  etiology,  61 
of  mosquitoes,  70,  104 

Gametes,  differentiation,  117,  122 

estivo-autumnal,  120 

quartan,  119 

tertian,  117 
Gastralgic  form,  214 
Gastro-intestinal  organs,  complications, 

235 


INDEX 


399 


Gastrointestinal  organs,  symptoms,  200 
Genito-urinary    organs,     complications, 
240 

symptoms,  200 
Geographic  distribution,  31 

of  hemoglobinuric  fever,  34 
Glossary  of  terms,  128 
Grabhamia,  97 
Ground  water,  43,  308 
Gymnometopa,  101 

Habits  of  mosquitoes,  104 
Haemamceba  immaculata,  119 
malarias,  118 
parva,  119 
praecox,  119 
quartanse,  118 
tertianae,  115 
vivax,  115 
Haematozoon  falciform,  120 
Haemocytozoa,  112 
Haemogogus,  101 
Haemomenas  praecox,  119 
Hayem's  method,  259 
Heart,  pathology,  177,  180,  183 
Hematuria.     See  Hemoglobinuric  jever. 
Hemiplegia,  209 

Hemoglobinuric     fever,     complications, 
226 
diagnosis,  289 
etiology,  153 

geographic  distribution,  34 
history,  23 
pathogenesis,  160 
pathology,  180 
prognosis,  297 
prophylaxis,  332 
quinine  and,  26 
sequela;,  226 
symptoms,  216 
treatment,  380 
Hemolysin,  199 
Hemosiderin,  174 
Hibernation  of  larvae,  107 
mosquitoes,  108 
ova,  107 
parasites,  71 
pupae,  108 
History  of  cinchona,  28 
of  hemoglobinuric  fever,  23 


History  of  malaria,  18 
Howardina,  101 
Human  cycle,  114 
Hydrophobic  form,  209 
Hygienic  treatment,  365 
Hypodermic  method,  359 

Idiosyncrasy,  156 
Imago  of  mosquitoes,  81 
Immunity,  50 

congenital,  54 
Incubation,  184 
Index  endemicus,  56 
Individual  predisposition,  151 
Infection,  modes  of,  63 
Influenza,  complication,  251 

diagnosis,  286 
Inheritance  of  parasites  by  mosquitoes, 

7i 
Inoculation,  67 
Insecticides,  312 

Intestines,  pathology,  176,  180,  182 
Intravenous  method,  363 
Introduction,  17 
Inundations,  47,  143 
Isolation  of  patients,  327 
Isostomyia,  99 

Janthtnosoma,  92 

Key  to  mosquitoes,  86 

Kidneys,  pathology,  176,  179,  182 

Killing  mosquitoes,  108 

Larv^,  differentiation,  79 

hibernation,  107 
Larval  stage,  duration,  79 
Latent  malaria,  228 

pathogenesis,  139 
Laverania  malariae,  118 

praecox,  119 
Leishman's  stain,  262 
Length  of  flight  of  mosquitoes,  105 

of  life  of  mosquitoes,  107 

of  residence,  59,  143,  157 
Lepidoplatys,  93 
Lepidosia,  92 
Leukemia,  diagnosis,  287 
Leukocytes,  197,  223,  279 
Life  of  mosquitoes,  length,  107 


400 


INDEX 


Limatus,  103 

Liver,  pathology,  175,  178,  181 
Localizations  of  parasites,  150 
Lungs,  pathology,  176,  180,  183 
Lutzia,  97 

Malaria  upon  ships,  49 

without  mosquitoes,  72 
Malaria-bearing  mosquitoes,  74 
Malarial  parasites,  112 
Malignant  tertian,  191 
Marshes,  43 
Masked  malaria,  232 
Megarhinae,  87,  89 
Megarhinus,  89 
Melanin,  174 
Melanoconion,  99 
Methods  of  administration,  357 
Methylene-blue,  373 
Micraedes,  99 

Microscopic  examination  of  blood,  258 
Midgut,  dissection,  no 
Mixed  infections,  193 
Modes  of  infection,  63 
Mononuclear  increase,  279 
Mortality,  295 

of  hemoglobinuric  fever,  298 

of  pernicious  malaria,  296 
Mounting  mosquitoes,  109 
Mythology  and  malaria,  18 
Myzomyia,  88 
Mosquito  cycle,  123 

larvae,  77 

pupae,  80 
Mosquitoes  as  malaria  carriers,  22 

classification,  86 

description  of  adult,  81 

destruction  of,  305 

hemoglobinuric  fever  and,  36 

hibernation  of,  108 

list  of  malaria-bearing,  74 

malaria-bearing,  69 

Negative  results,  277 

Negro,  141,  253 

Nephritis,  240 

Nervous  system,  complications,  243 

symptoms,  202 
Nobel  prizes,  18 


Nocht-Romanowsky  stain,  262 
Notes  of  mosquitoes,  105 
Nototricha,  89 
Number  of  parasites,  147 

Objections  to  mosquito  theory,  72 
Occasional    causes    of   hemoglobinuria, 

159 
Occupation,  60,  143,  159 
Ochlerotatus,  93 
Odors  and  mosquitoes,  106 
Opium-eating  and  immunity,  62 
Ova,  hibernation,  107 

of  anopheles,  76 

of  mosquitoes,  107 
Overflows,  47,  143 
Oviposition  of  mosquitoes,  107 

Palmate  hairs  of  larvae,  78 
Parasites,  biology,  113 

classification,  112 

estivo-autumnal,  119 

in  hemoglobinuric  fever,  161 

localizations,  150 

number,  150 

quartan,  118 

table  of  differentiation,  122 

tertian,  115 
Paroxysm,  description,  184 
Parthenogametes,  126 
Parthenogenesis,  139,  229 

in  mosquitoes,  107 
Parthenogenetic  cycle,  114,  124 
Pathogenesis,  129 

of  hemoglobinuric  fever,  160 

of  pernicious  malaria,  145 
Pathology,  174 

of  hemoglobinuric  fever,  180 
Pericardium,  pathology,  183 
Periodicity,  256 
Peritonitis,  215 

Pernicious  malaria,  diagnosis,  287 
etiology,  140 
prognosis,  295 
symptoms,  203 
treatment,  378 
Perpetuation  of  parasites,  71 
Petroleum  in  prophylaxis,  309 
Phagocytosis,  224 


INDEX 


40I 


Phoniomyia,  103 

Physiologic  effects  of  quinine,  349 

Pigment,  278 

Plants  and  malaria,  48 

Plasmodium  falciparum,  120 

immaculatum,  119 

malariae,  118 

prascox,  119 

vivax,  115 
Pleurae,  pathology,  183 
Pneumaculex,  101 
Pneumonic  form,  211 
Positive  results,  275 
Postmalarial  fever,  194 
Pregnancy,  55,  242 

and  quinine,  353 
Previous  attacks  of  hemoglobinuric  fever, 
156 

of  malaria,  144 
Private  prophylaxis,  332 
Prodromata,  185 
Prognosis,  292 

of  hemoglobinuric  fever,  297 

of  pernicious  malaria,  295 
Prophylaxis,  302 

of  hemoglobinuric  fever,  332 
Psorophora,  90 
Psorophorinae,  87,  90 
Puerperal  septicemia,  diagnosis,  285 
Puerperium,  55 
Pupae,  80 

differentiation,  80 

hibernation,  108 

Quartan  infection,  symptoms,  189 

parasite,  118 
Quinine,  334 

absorption  and  elimination,  335 

action  on  parasites,  341 

and  pregnancy,  353 

contra-indications,  355 

effect  on  parasites,  271 

in  etiology  of  hemoglobinuric  fever,  26, 
164 

methods  of  administration,  357 

physiologic  effects,  349 

prophylaxis,  316 

substitutes,  372 

test,  281 
Quotidian  estivo-autumnal,  192 
26 


Race,  50,  253 

and  hemoglobinuric  fever,  154 

and  pernicious  malaria,  141 
Rainfall,  41 

Rectal  administration,  364 
Relapse,  228 

in  pernicious  malaria,  207 

pathogenesis,  139 
Residence,  change  of,  143,  158 

length  of,  59,  143,  157 
Respiratory  system,   complications,   233 

symptoms,  199 
Resting  position  of  larvae,  79 

of  mosquitoes,  84 
Rice  culture,  60 
Ring  forms,  differentiation,  123 
Romanowsky  stain,  261 
Rupture  of  spleen,  239 

Sabethes,  103 
Sabethoides,  103 
Salivary  glands,  dissection,  11 1 
Salt  marshes,  45 

water  and  mosquitoes,  75 
Schizogonic  cycle,  114 
Schuffner's  dots,  197 
Screens,  322 
Season,  39 

and  hemoglobinuric  fever,  156 

and  mosquitoes,  103 

and  pernicious  malaria,  142 
Secondary  fever,  194 
Sequelae,  232 

of  hemoglobinuric  fever,  226 
Sex,  54 

and  hemoglobinuric  fever,  155 

and  pernicious  malaria,  141 
Ships,  malaria  on,  49 
Sitting  position  of  mosquitoes,  84 
Skin  complications,  248 

symptoms,  202 
Smallpox,  complication,  252 
Social  condition,  61,  144 
Soil,  42 

Solubility  of  quinine  salts,  334 
Sources  of  error,  268 
Spleen,  abscess  of,  240 

pathology,  175,  178,  181 

rate,  58 

rupture  of,  239 


402 


INDEX 


Splenic  enlargement,  pathogenesis,  140 
Spodogenous  fever,  194 
Spontaneous  recovery,  292 

pathogenesis,  140 
Sporogonic  cycle,  123 
Stegomyia,  93 
Stippling,  196 

Stomach,  pathology,  176,  180,  182 
Study  of  mosquitoes,  108 
Substitutes  for  quinine,  372 
Sudoral  form,  214 
Surgical  aspect,  254 
Swamps,  43 
Symptoms,  184 

analysis,  193 

of  hemoglobinuric  fever,  216 

of  pernicious  malaria,  203 
Symptomatic  treatment,  367 
Syncopal  form,  214 
Syphilis,  complication,  252 

T^NIOKRHYNCHUS,   IOO 

Technic  of  blood  examination,  258 

of  mosquito  study,  108 
Temperature,  atmospheric,  38 

and  mosquitoes,  103 

clinical,  193,  218 
Tertian  estivo-autumnal,  191 

infection,  symptoms,  187 

parasite,  115 
Tetanic  form,  209 
Texas  fever,  162 
Theobaldia,  98 
Therapeutic  test,  281 
Thick  film  process,  268 
Thoracic  forms,  211 
Time  of  administration,  365 
Tinolestes,  99 
Topography,  43 


Toxin,  130,  151 

in  hemoglobinuric  fever,  163 
Treatment,  334 

of  hemoglobinuric  fever,  380 

of  pernicious  malaria,  378 
Trees,  effect  on  malaria,  48 

in  prophylaxis,  309 
Trichoprosopon,  102 
Trichoprosoponinas,  87,  102 
Tuberculosis,  complication,  251 

diagnosis,  286 
Typhoid  fever,  complication,  250 
diagnosis,  285 
form,  210 

Uninhabited  regions,  malaria  in,  74 
Unity  of  the  malarial  parasites,  113 
Uranotffinia,  102 
Uranotseniinae,  87,  102 
Urine,  200,  219 

Vegetation,  48 
Verrallina,  93 
Volcanic  eruptions,  46 

Water,  contagion  through,  62 
Weeds  and  malaria,  48 
Wind,  malaria  borne  by,  48 
mosquitoes  borne  by,  106 
Wings  of  mosquitoes,  83 
Wright's  stain,  263 
Wyeomyia,  103 

Yellow  fever  and  hemoglobinuric  fever, 
28 
diagnosis,  291 

Zoologic    relations    of    the    parasites, 


SAUNDERS'  BOOKS 


on 


Practice,  Pharmacy, 
Materia  Medica,  Thera- 
peutics, Pharmacology, 
and  the  Allied  Sciences 


W.  B.  SAUNDERS   COMPANY 

925  WALNUT  STREET  PHILADELPHIA 

9,  HENRIETTA  STREET,  COVENT  GARDEN,   LONDON 

SAUNDERS'  SUCCESSFUL  PUBLISHING 

AS  is  well-known,  the  lists  of  most  publishers 
contain  a  number  of  books  that  have  never 
paid,  and  for  which  the  publisher  will  never  get 
back  the  money  invested.  Messrs.  W.  B.  Saunders 
Company  would  call  attention  to  the  fact  that 
they  have  no  such  works  on  their  list.  In  all  the 
years  of  their  business  experience  they  have  never 
published  a  book  at  a  loss.  This  they  confidently 
consider  a  most  remarkable  record,  and  submit  the 
fact  to  the  attention  of  the  profession  as  an  example 
of  what  might  justly  be  called  "  Successful  Pub- 
lishing." 

A  Complete  Catalogue  of  our  Publications  will  be  Sent  upon  Request 


SAUNDERS'    BOOKS    ON 


Musser  and   Kelly  on 
Treatment 

A  Handbook  of  Treatment.  By  j6  eminent  specialists.  Edited 
by  John  H.  Musser*  M.  D.,  Professor  of  Clinical  Medicine,  University 
of  Pennsylvania ;  and  A.  O.  J.  Kelly,  M.  D.,  Assistant  Professor  of 
Clinical  Medicine,  University  of  Pennsylvania.  Three  octavo  volumes 
of  about  650  pages  each,  illustrated. 

READY  IN  JULY— IN  THREE  VOLUMES 
A   PRACTICE   FOR  QUICK   REFERENCE   AND   DAILY  USE 

Every  chapter  in  this  work  was  written  by  a  specialist  of  unquestioned  authority. 
Not  only  is  drug  therapy  given  but  also  dietotherapy,  serumtherapy,  organo- 
therapy, rest-cure,  exercise  and  massage,  hydrotherapy,  climatology,  electro- 
therapy, .r-ray,  and  radial  activity  are  fully,  clearly,  and  definitely  discussed. 
Those  measures  partaking  of  a  surgical  nature  have  been  presented  by  surgeons* 


THE    EMINENT   CONTRIBUTORS 


Isaac  A.  Abt,  M.D. 
Sir  Clifford  Allbutt,  M.D. 
James  M.  Anders,  M.D. 
Lewellys  F.  Barker,  M.D. 
Joseph  C.  Bloodgood,  M.D. 
George  Blumer,  M.D. 
Sir  Lauder  Brunton,  M.D. 
Charles  W.  Burr,  M.D. 
Richard  C.  Cabot,  M.D. 
James  F.  Carroll,  M.D. 
John  G.  Clark,  M.D. 
Rufus  I.  Cole,  M.D. 
Warren  Coleman,  M.D. 
Matthew  H.  Cryer,  M.D. 
Clinton  T.  Dent,  M.D. 
Francis  X.  Dercum,  M.D. 


John  H.  Gibbon,  M.D. 
Joel  E.  Goldthwait,  M.  D. 
Samuel  McC.  Hamill,  M.D. 
Hobart  A.  Hare,  M.D. 
Charles  Harrington,  M.D. 
Ludvig  Hektoen,  M.D. 


George  P.  Muller,  M.D. 
John  H.  Musser,  M.D. 
William  Osier,   M.D. 
Edward  O.  Otis,  M.D. 
Henry  K.  Pancoast,  M.D. 
RoswellPark,-M.D. 


Albion  Walter  Hewlett,  M.D.  Richard  M.  Pearce,  M.D. 


Guy  Hinsdale,  M.D. 
Guy  L.  Hunner,  M.D. 
Chevalier  Jackson,  M.D. 
Henry  Jackson,  M.D. 
Theodore  C.  Janeway,  M.  D. 
J.  H.  Jobson,  M.D. 
A.  0.  J.  Kelly,  M.D. 
Maynard  Ladd,  M.D. 
Egbert  Lefevre,  M.D. 


George  E.  deSchweinitz,  M.D.  James  Henry  Lloyd,  M.D. 


George  Dock,  M.D. 
Isadore  Dyer,  M.D. 
David  L.  Edsall,  M.D. 
William  A.  Edwards,  M.D. 
Arthur  W.  Elting,  M.D. 
John  M.  T.  Finney,  M.D. 
Charles  H.  Frazier,  M.D. 
M.  Howard  Fussell,  M.D. 
Thomas  B.  Futcher,  M.D. 


G.  Hudson  Makuen,  M.D. 
Charles  F.  Martin,  M.  D. 
Edward  Martin,  M.D. 
Charles  W.  Mayo,  M.D. 
William  J.  Mayo,  M.D. 
R.  Tait  McKenzie,  M.D. 
Herbert  C.  Moffitt,  M.D. 
Jesse  M.  Mosher,  M.D. 
B.  G.  A.  Moynihan,  Esq. 


Charles  W.  Richardson,  M.D. 
David  Riesman,  M.D. 
Milton  J.  Rosenau,  M.D. 
Joseph  Sailer,  M.D. 
J.  F.  Schamberg,  M.D. 
Henry  Sewall,  M.D. 
Bertram  W.  Sippy,  M.D. 
William  G.  Spiller,  M.D. 
J.  Dutton  Steele,  M.D. 
Alfred  Stengel,  M.D. 
Charles  G.  Stockton,  M.D. 
James  E.  Talley,  M.D. 
E.  W.  Taylor,  M.D. 
James  Tyson,  M.D. 
George  H.  Weaver,  M.D. 
J.  William  White,  M.D. 
Alfred  C.Wood,  M.D. 
Horatio  C.  Wood,  Jr.,  M.D. 


PRACTICE   OF  MEDICINE 


Kemp  on 
Stomach  and  Intestines 

Diseases  of  the  Stomach  and  Intestines.  By  Robert  Coleman 
Kemp,  M.  D.,  Professor  of  Gastro-intestinal  Diseases  at  the  New 
York  School  of  Clinical  Medicine.  Octavo  of  766  pages,  with  279 
illustrations.     Cloth,  $6.00  net;  Half  Morocco,  $7.50  net. 

JUST   READY— MEDICAL  AND   SURGICAL 

Of  the  many  works  on  gastro-intestinal  diseases,  this  is  perhaps  the  only  one 
in  which  the  needs  of  the  general  practitioner  are  given  pre-eminent  emphasis. 
It  is  the  practitioner  who  first  meets  with  these  cases,  and  it  is  he  upon  whom  the 
burden  of  diagnosis  rests.  After  the  diagnosis  is  established,  the  practitioner,  if 
properly  equipped,  could  frequently  treat  the  case  himself  instead  of  transferring 
it  to  a  specialist.  This  work  is  intended  to  equip  the  practitioner  with  this  end  in 
view.  As  visceral  displacements  have  assumed  such  an  important  position,  their 
symptoms,  diagnosis,  and  treatment,  notably  by  mechanical  methods,  are  specially 
described.  Auto-intoxication  has  been  given  unusual  attention.  Typhoid  fever 
is  also  included  because  of  its  local  manifestations. 


Deaderick     on     Malaria 

Practical  Study  of  Malaria.  By  William  H.  Deaderick,  M.  D., 
Member  American  Society  of  Tropical  Medicine ;  Fellow  London 
Society  of  Tropical  Medicine  and  Hygiene.  Octavo  of  402  pages, 
illustrated.     Cloth,  $4.50  net ;  Half  Morocco,  $6.00  net. 

JUST  READY— A  WORK  LONG  NEEDED 

This  is  a  practical  work,  one  laying  special  stress  on  diagnosis  and  treatment, 
and  one,  therefore,  that  will  prove  of  the  greatest  service.  It  is  the  only  book 
in  any  language  describing  the  third  cycle  of  the  malarial  parasite — the  par- 
thenogenetic  cycle — and  the  account  given  of  hemoglobinuric  fever  is  full  and 
clear.  The  chapters  on  diagnosis  and  treatment  are  conspicuous  for  the  clear- 
ness of  expression,  the  exactness  of  statement,  and  the  intuitive  way  in  which 
the  author  has  grasped  the  needs  of  the  physician  and  supplied  them.  It  is  a 
necessary  book — one  that  you  will  want. 

Frank  A.  Jones,  M.  D. 

Professor  of  Clinical  Medicine  and  Physical  Diagnosis,  Memphis  Hospital  Medical  College. 

"  Dr.  Deaderick's  book  is  up  to  date  and  the  subject  matter  is  well  arranged.  We  have 
been  waiting  for  many  years  for  such  a  work  written  by  a  man  who  sees  malaria  in  all  its  forms 
in  a  highly  malarious  climate." 


SAUNDERS'     BOOKS    ON 


Bonney  on  Tuberculosis 


Tuberculosis.  By  Sherman  G.  Bonney,  M.  D.,  Professor  of 
Medicine,  Denver  and  Gross  College  of  Medicine,  Denver.  Octavo 
of  955  pages,  with  243  original  illustrations.     Cloth,  $7.00  net. 

JUST  READY— THE  NEW  (2di   EDITION 

Dr.  Bonney' s  work  embodies  the  results  of  wide  personal  experience  in  ob- 
serving and  treating  tuberculous  patients,  especially  those  suffering  from  the 
pulmonary  form.  His  book  is  a  thorough  and  complete  treatise  of  the  entire  sub- 
ject of  tuberculosis,  taking  up  every  region  of  the  body  and  every  secondary 
involvement  that  can  occur.  The  section  on  Physical  Signs  of  Pulmonary 
Tuberculosis  is  really  a  complete  monograph  on  the  physical  diagnosis  of  diseases 
of  the  chest.  As  is  to  be  expected,  treatment  is  particularly  full  and  practical. 
There  are  chapters  on  prophylaxis  ;  open-air  treatment,  fully  illustrated  ;  diet  ; 
sanitarium  and  climatic  treatments  ;  therapeutic  measures  to  alleviate  distress- 
ing symptoms  ;  and  drug  and  vaccine  therapeutics.  There  are  nearly  two  hun- 
dred original  pictures,  including  twenty  in  colors  and  sixty  .r-ray  photographs. 

Maryland  Medical  journal 

"  Dr.  Bonney's  book  is  one  of  the  best  and  most  exact  works  on  tuberculosis,  in  all  its 
aspects,  that  has  yet  been  published." 


Anders   and    Boston's   Diagnosis 


A  Text=Book  of  Diagnosis.  By  James  M.  Anders,  M.  D.,  Ph.D., 
LL.  D.,  Professor  of  the  Theory  and  Practice  of  Medicine  and  of  Clinical 
Medicine,  Medico-Chirurgical  College,  Philadelphia  ;  and  L.  Napoleon 
Boston,  M.  D.;  Adjunct  Professor  of  Medicine,  Medico-Chirurgical 
College,  Philadelphia.  Octavo  of  1200  pages,  with  300  original  illus- 
trations. 

READY  IN  JULY— FOR  THE  PRACTITIONER 

This  new  work  is  designed  expressly  for  the  general  practitioner.  The 
methods  given  are  practical  and  especially  adapted  for  quick  reference.  The 
diagnostic  methods  are  presented  in  a  forceful,  definite  way  by  men  who  have 
had  wide  experience  at  the  bedside  and  in  the  clinical  laboratory.  The  text  is 
profusely  illustrated  with  original  pictures,  each  one  representing  some  point  in 
technic  or  some  diagnostic  sign.      It  is  a  work  for  every  practitioner. 


THE  PRACTICE   OF  MEDICINE 


Anders' 
Practice   of  Medicine 


A  Text=Book  of  the  Practice  of  Medicine.  By  James  M.  Anders, 
M.  D.,  Ph.  D.,  LL.  D.,  Professor  of  the  Practice  of  Medicine  and  of 
Clinical  Medicine,  Medico-Chirurgical  College,  Philadelphia.  Hand- 
some octavo,  1326  pages,  fully  illustrated.  Cloth,  $5.50  net;  Half 
Morocco,  $7.00  net. 

JUST   READY— THE   NEW    (9th)    EDITION 

The  success  of  this  work  is  no  doubt  due  to  the  extensive  consideration  given 
to  Diagnosis  and  Treatment,  under  Differential  Diagnosis  the  points  of  distinction 
of  simulating  diseases  being  presented  in  tabular  form.  In  this  new  edition 
Dr.  Anders  has  included  all  the  most  important  advances  in  medicine,  keeping 
the  book  within  bounds  by  a  judicious  elimination  of  obsolete  matter.  A  great 
many  articles  have  also  been  rewritten. 

Wm.  E.  Qtrine,  M.  D., 

Professor  of  Medicine  and  Clinical  Medicine,  College  of  Physicians  and  Surgeons,  Chicago. 
"  I  consider  Anders'  Practice  one  of  the  best  single-volume  works  before  the  profession  at 
this  time,  and  one  of  the  best  text-books  for  medical  students." 


DaCosta's  Physical   Diagnosis 

Physical  Diagnosis.     By  John  C.  DaCosta,  Jr.,  M.  D.,  Associate 
in  Clinical  Medicine,  Jefferson  Medical  College,  Philadelphia.     Octavo 
°f  557  Pages>  witn  2I2  original  illustrations.     Cloth,  $3.50  net. 
ORIGINAL   ILLUSTRATIONS 

Dr.  DaCosta's  work  is  a  thoroughly  new  and  original  one.  Every  method 
given  has  been  carefully  tested  and  proved  of  value  by  the  author  himself. 
Normal  physical  signs  are  explained  in  detail  in  order  to  aid  the  diagnostician  in 
determining  the  abnormal.  Both  direct  and  differential  diagnosis  are  emphasized. 
The  cardinal  methods  of  examination  are  supplemented  by  full  descriptions  of 
technic  and  the  clinical  utility  of  certain  instrumental  means  of  research. 

Dr.   Henry  L.   Eisner,   Professor  of  Medicine  at  Syracuse  University. 

"  I   have  reviewed  this  book,  and  am  thoroughly  convinced  that  it  is  one  of  the  best  ever 
written  on  this  subject.     In  every  way  I  find  it  a  superior  production." 


SAUNDERS'  'BOOKS   ON 


Tousey's 

Medical  Electricity  and  X-Rays 

Medical  Electricity  and  the  X=Rays.  By  Sinclair  Tousey,  M.  D., 
Consulting  Surgeon  to  St.  Bartholomew's  Hospital,  New  York.  Octavo 
of  1 1 16  pages,  with  750  practical  illustrations,  16  in  colors. 

Cloth,  $7.00  net ;  Half  Morocco,  $8.50  net. 

JUST  READY— FOR  THE  PRACTITIONER 

This  new  work  by  such  an  eminent  authority  is  destined  to  take  a  leading 
place  among  books  on  this  subject.  Written  primarily  for  the  general  prac- 
titioner, it  gives  him  just  the  information  he  wishes  to  have  regarding  the  use  of 
medical  electricity,  the  therapeutic  results  obtained,  etc.  At  the  same  time  it 
tells  the  specialist  how  the  most  eminent  electrotherapeutists  are  securing  results, 
the  latest  authorities  in  every  country  having  been  consulted  for  details  of  prac- 
tical value.  The  work  gives  explicit  directions  for  the  care  and  regulation  of 
static  machines,  x-ray  tubes,  and  all  apparatus.  Recognizing  that  the  production 
of  a  good  radiograph  every  time,  without  risk  to  patient  or  apparatus,  is  of  the 
utmost  importance,  the  author  tells  how  to  make  x-ray,  pictures  by  a  practical 
technic  easily  followed,  even  though  the  operator  be  inexperienced  in  this  field. 
Dental  radiography  the  author  has  made  his  own.  X-ray  dosage  is  fully  con- 
sidered. 

McKenzie  on  Exercise  in 
Education   and    Medicine 

Exercise  in  Education  and  Medicine.  By  R.  Tait  McKenzie,  B.  A., 
M.  D.,  Professor  of  Physical  Education  and  Director  of  the  Department, 
University  of  Pennsylvania.  Octavo  of  393  pages,  with  346  original 
illustrations.  Cloth,  $3.50  net. 

RECENTLY  ISSUED 

This  work  is  a  full  and  detailed  treatise  on  the  application  of  systematized 
exercise  in  the  development  of  the  normal  body  and  in  the  correction  of  certain 
diseased  conditions  in  which  gymnastics  have  proved  of  value. 

D.  A.   Sarg'eant,   M.   D.,   Director  of  Hemenway  Gymnasium,  Harvard  University. 

"  It  cannot  fail  to  be  helpful  to  practitioners  in  medicine.  The  classification  of  athletic 
games  and  exercises  in  tabular  form  for  different  ages,  sexes,  and  occupations  is  the  work  of  an 
expert.     It  should  be  in  the  hands  of  every  physical  educator  and  medical  practitioner." 


PRACTICE    OF  MEDICINE 


Oertel  on  Bright's  Disease 

The  Anatomical  and  Histological  Processes  of  Bright's  Disease. — 

By  Horst  Oertel,  M.  D.,  Director  of  the  Russell  Sage  Institute  of 

Pathology,  New  York.     Octavo  of  300  pages,  with  50  illustrations  and 

6  colored  plates. 

READY  IN  JUNE 

These  lectures  deal  with  the  anatomic  and  histologic  processes  of  Bright's 
disease,  and  in  a  somewhat  different  way  from  the  usual  manner.  Everywhere 
relations  are  emphasized  and  an  endeavor  made  to  reconstruct  the  whole  as  a 
unit  of  interwoven  processes.  In  the  preparation  of  his  lectures  the  author  had  in 
mind  a  twofold  aim  :  To  present  the  visual  picture  of  nephritis  and  to  prepare  the 
proper  way  for  the  understanding  of  the  genesis  of  the  disease. 


Fenwick  on  Dyspepsia 

Dyspepsia By    William   Soltau   Fenwick,  M.  D.,  of  London, 

England.     Octavo  volume  of  400  pages,  illustrated. 

JUST   ISSUED 

Dr.  Fenwick  takes  up  this  important  disease  in  a  thoroughly  systematic  way. 
He  discusses  the  causes,  pathology,  symptoms,  diagnosis,  prognosis,  and  treat- 
ment with  a  clearness,  a  definiteness,  and,  withal,  a  conciseness  that  makes  his 
work  the  most  practical  and  useful  on  this  subject.  Dyspepsia  is  a  condition  so 
frequently  met  with  by  every  practitioner  that  this  work  will  undoubtedly  appeal 
most  strongly  as  supplying  a  need  long  felt.      The  text  is  illustrated. 


Slade's  Physical  Examination  and 
Diagnostic  Anatomy  READY  ,NJULY 

Physical  Examination  and  Diagnostic  Anatomy.— By  Charles  B. 
Slade,  M.  D.,  Chief  of  Clinic  in  General  Medicine,  University  and 
Bellevue  Hospital  Medical  College.     1 2mo  of  200  pages,  illustrated. 

This  work  is  intended  to  serve  as  a  text-book  on  the  technic  and  fundamental 
methods  and  principles  of  Physical  Examination.  The  subject  matter  is  arranged 
to  accord  with  the  natural  course  the  average  student  pursues  in  acquiring  knowl- 
edge of  this  subject.  The  first  thought  in  the  preparation  of  the  book  was  to 
make  it  practical.  Exhaustive  discussion  and  problems  of  diagnosis  have  been 
avoided,  rather  holding  the  attention  of  the  student  to  the  essential  principles  of 
the  subject.     The  illustrations,  too,  have  been  drawn  with  the  practical  in  mind. 


SAUNDERS'  BOOKS  ON 


Sahli's  Diagnostic  Methods 

Editors :  Francis  P.Kinnicutt,  M.D.,  and  Nath'l  Bowditch  Potter,  M.D. 


A  Treatise  on  Diagnostic  Methods  of  Examination.  By  Prof. 
Dr.  H.  Sahli,  of  Bern.  Edited,  with  additions,  by  Francis  P.  Kinni- 
cutt,  M.  D.,  Professor  of  Clinical  Medicine,  Columbia  University,  N.  Y. ; 
and  Nath'l  Bowditch  Potter,  M.  D.,  Associate  in  Clinical  Medicine, 
Columbia  University.  Octavo  of  1008  pages,  profusely  illustrated. 
Cloth,  $6.50  net;  Half  Morocco,  $8.00  net. 

ILLUSTRATED 

Dr.  Sahli's  great  work,  upon  its  publication  in  German,  was  immediately- 
recognized  as  the  most  important  work  in  its  field.  Not  only  are  all  methods 
of  examination  for  the  purpose  of  diagnosis  exhaustively  considered,  but  the  ex- 
planation of  clinical  phenomena  is  given  and  discussed  from  physiologic  as  well 
as  pathologic  points  of  view.  In  the  chemical  examination  methods  are  described 
so  exactly  that  it  is  possible  for  the  clinician  to  work  according  to  these  directions. 

Lewellys  F.  Barker,  M.  D. 

Professor  of  the  Principles  and  Practice  of  Medicine,  Johns  Hopkins  University 
"  I  am  delighted  with  it,  and  it  will  be  a  pleasure  to  recommend  it  to  our  students  in  the 
Johns  Hopkins  Medical  School." 


Friedenwald  and  Ruhrah 
on  Diet 


Diet  in  Health  and  Disease.  By  Julius  Friedenwald,  M.  D., 
Professor  of  Diseases  of  the  Stomach,  and  John  Ruhrah,  M.  D.,  Pro- 
fessor of  Diseases  of  Children,  College  of  Physicians  and  Surgeons, 
Baltimore.     Octavo  of  764  pages.     Cloth,  $4.00  net. 

THE  NEW  (3d)   EDITION 

This  new  edition  has  been  carefully  revised,  making  it  still  more  useful  than  the  two 
editions  previously  exhausted.  The  articles  on  milk  and  alcohol  have  been  rewritten,  additions 
made  to  those  on  tuberculosis,  the  salt-free  diet,  and  rectal  feeding,  and  several  tables  added, 
including  Winton's,  showing  the  composition  of  diabetic  foods. 

George  Dock,  M.  D. 

Professor  of  Theory  and  Practice  and  of  Clinical  Medicine,    Tulane   University. 
"  It  seems  to  me  that  you  have  prepared  the  most  valuable  work  of  the  kind  now  available. 
I  am  especially  glad  to  see  the  long  list  of  analyses  of  different  kinds  of  foods." 


THERAPEUTICS  AND  MATERIA  MEDICA 


Hinsdale's   Hydrotherapy 

Hydrotherapy :  A  Treatise  on  Hydrotherapy  in  General ;  Its 
Application  to  Special  Affections ;  the  Technic  or  Processes  Employed, 
and  a  Brief  Chapter  on  the  Use  of  Waters  Internally.  By  Guy  Hins- 
dale, M.D.,  Lecturer  on  Climatology  at  the  Medico-Chirurgical  College 
of  Philadelphia.     Octavo  of  500  pages,  illustrated. 

READY  IN  JUNE 

The  treatment  of  disease  by  hydrotherapeutic  measures  has  assumed  such  an. 
important  place  in  medical  practice  that  a  good,  practical  work  on  the  subject 
is  an  essential  in  every  practitioner's  armamentarium.  This  new  work  supplies 
all  needs.  It  describes  fully  the  various  kinds  of  baths,  douches,  sprays  ;  the 
application  of  heat  and  cold  ;  the  internal  use  of  mineral  waters  and  all  ot'her 
procedures  included  under  hydrotherapeutic  measures.  Then  the  use  of  hydro- 
therapy in  the  various  diseases  is  detailed  concisely,  yet  explicitly  and  adequately. 
Illustrations  have  been  freely  used  throughout  the  text.  As  a  practical  work  on 
this  important  subject,  Dr.  Hinsdale's  book  will  be  found  to  take  first  place. 


Swan's   Prescription-writing 
and  Formulary  juST  ready 

Prescription-writing  and  Formulary.  By  John  M.  Swan,  M.  D., 
Associate  Professor  of  Clinical  Medicine  in  the  Medico-Chirurgical 
College  of  Philadelphia.      i2mo  of  185  pages.     Flexible  leather,  $1.25  net. 

This  work  contains  nearly  1050  prescriptions,  selected  because  of  their  proved 
value.  There  is  also  other  information  often  needed  by  the  practitioner,  such  as 
prescription  Latin,  a  chapter  on  the  United  States  Pharmacopeia  and  its  official 
preparations,  tables  of  weights  and  measures,  doses,  incompatibility  and  number 
of  ingredients,  abbreviations,  and  miscellaneous  considerations. 


Stewart's  Pocket  Therapeu- 
tics and  Dose-book    NEW  gffusss; 

Pocket  Therapeutics  and  Dose=book.  By  Morse  Stewart,  Jr., 
M.  D.     32mo  of  263  pages.  Cloth,  $1.00  net. 

This  little  book  is  a  complete  therapeutics  as  well  as  a  dose-book,  and  it  is 
so  arranged  that  the  information  sought  can  be  obtained  at  a  glance.  The  work 
for  this  edition  has  been  practically  rewritten  and  entirely  reset.     It  fits  the  pocket. 


io  SAUNDERS'  BOOKS  ON 

AMERICAN   EDITION 

NOTHNAGEL'S  PRACTICE 

UNDER   THE    EDITORIAL    SUPERVISION   OF 

ALFRED    STENGEL,    M.D. 

Professor  of  Clinical  Medicine  in  the  University  of  Pennsylvania 


Typhoid  and  Typhus  Fevers 

By  Dr.  H.  Curschmann,  of  Leipsic.  Edited,  with  additions,  by  William 
Osler,  M.  D.,  F.  R.  C.  P.,  Regius  Professor  of  Medicine,  Oxford  University, 
Oxford,  England.      Octavo  of  646  pages,  illustrated. 

Smallpox  (including  Vaccination),  Varicella,  Cholera  Asiatica, 
Cholera  Nostras,  Erysipelas,  Erysipeloid,  Pertussis,  and 
Hay  Fever 

By  Dr.  H.  Immermann,  of  Basle  ;  Dr.  Th.  von  Jurgensen,  of  Tubingen  ; 
Dr.  C.  Liebermeister,  of  Tubingen ;  Dr.  H.  Lenhartz,  of  Hamburg ; 
and  Dr.  G.  Sticker,  of  Giessen.  The  entire  volume  edited,  with  additions, 
by  Sir  J.  W.  Moore,  M.  D.,  F.  R.  C.  P.  I.,  Professor  of  Practice,  Royal  Col- 
lege of  Surgeons,  Ireland.      Octavo  of  682  pages,  illustrated. 

Diphtheria,  Measles,  Scarlet  Fever,  and  Rotheln 

By  William  P.  Northrup,  M.  D.,  of  New  York,  and  Dr.  Th.  von  Jur- 
gensen, of  Tubingen.  The  entire  volume  edited,  with  additions,  by  William 
P.  Northrup,  M.  D.,  Professor  of  Pediatrics,  University  and  Bellevue  Hos- 
pital Medical  College,  New  York.  Octavo  of  672  pages,  illustrated,  including 
24  full-page  plates,  3  in  colors. 

Diseases  of  the  Bronchi,  Diseases  of  the  Pleura,  and  Inflam- 
mations of  the  Lungs 

By  Dr.  F.  A.  Hoffmann,  of  Leipsic ;  Dr.  O.  Rosenbach,  of  Berlin ;  and 
Dr.  F.  Aufrecht,  of  Magdeburg.  The  entire  volume  edited,  with  additions, 
by  John  H.  Musser,  M.  D.,  Professor  of  Clinical  Medicine,  University  of 
Pennsylvania.  Octavo  of  1029  pages,  illustrated,  including  7  full-page  colored 
lithographic  plates. 

Diseases  of  the  Pancreas,  Suprarenals,  and  Liver 

By  Dr.  L.  Oser,  of  Vienna  ;  Dr.  E.  Neusser,  of  Vienna  ;  and  Drs.  H. 
Ouincke  and  G.  Hoppe-Seyler,  of  Kiel.  The  entire  volume  edited,  with 
additions,  by  Reginald  H.  Fritz,  A.  M.,  M.  D.,  Hersey  Professor  of  the 
Theory  and  Practice  of  Physic,  Harvard  University  ;  and  Frederick  A. 
Packard,  M.  D.,  Late  Physician  to  the  Pennsylvania  and  Children's  Hos- 
pitals, Philadelphia.      Octavo  of  918  pages,  illustrated. 

SOLD  SEPARATELY— PER  VOLUME:  CLOTH,  $5.00  NET;    HALF  MOROCCO,  $6.00  NET 


PRACTICE    OF  MEDICINE  1 1 

AMERICAN   EDITION 

NOTHNAGEL'S  PRACTICE 

Diseases  of  the  Stomach 

By  Dr.  F.  Riegel,  of  Giessen.  Edited,  with  additions,  by  Charles  G. 
Stockton,  M.  D. ,  Professor  of  Medicine,  University  of  Buffalo.  Octavo  of 
835  pages,  with  29  text-cuts  and  6  full-page  plates. 

Diseases  of  the  Intestines  and  Peritoneum  Second  Edition 

By  Dr.  Hermann  Nothnagel,  of  Vienna.  Edited,  with  additions,  by 
H.  D.  Rolleston,  M.  D.,  F.  R.  C.  P.,  Physician  to  St.  George's  Hospital, 
London.      Octavo  of  1 100  pages,  illustrated. 

Tuberculosis  and  Acute  General  Miliary  Tuberculosis 

By  Dr.  G.  Cornet,  of  Berlin.  Edited,  with  additions,  by  Walter  B. 
James,  M.  D.,  Professor  of  the  Practice  of  Medicine,  Columbia  University, 
New  York.     Octavo  of  806  pages. 

Diseases  Of  the  Blood    [Anemia,  Chlorosis,  Leukemia,  and  Pseudoleukemia) 

By  Dr.  P.  Ehrlich,  of  Frankfort-on-the-Main  ;  Dr.  A.  Lazarus,  of  Char- 
lottenburg ;  Dr.  K.  von  Xoorden,  of  Frankfort-on-the-Main  ;  and  Dr. 
Felix  Pinkus,  of  Berlin.  The  entire  volume  edited,  with  additions,  by  Alfred 
Stengel,  M.  D.,  Professor  of  Clinical  Medicine,  LTniversity  of  Pennsylvania. 
Octavo  of  714  pages,  with  text-cuts  and  13  full-page  plates,  5  in  colors. 

Malarial  Diseases,  Influenza,  and  Dengue 

By  Dr.  J.  Mannaberg,  of  Vienna,  and  Dr.  O.  Leichtenstern,  of  Cologne. 
The  entire  volume  edited,  with  additions,  by  Ronald  Ross,  F.  R.  C.  S.  (Eng.), 
F.  R.  S.,  Professor  of  Tropical  Medicine,  University  of  Liverpool  ;  J.  W.  W. 
Stephens,  M.  D.,  D.  P.  H.,  Walter  Myers  Lecturer  on  Tropical  Medicine, 
University  of  Liverpool  ;  and  Albert  S.  Grunbaum,  F.  R.  C.  P.,  Professor 
of  Experimental  Medicine,  University  of  Liverpool.  Octavo  of  769  pages, 
illustrated. 

Diseases  of  Kidneys  and  Spleen,  and  Hemorrhagic  Diatheses 

By  Dr.  H.  Senator,  of  Berlin,  and  Dr.  M.  Litten,  of  Berlin.  The  entire 
volume  edited,  with  additions,  by  James  B.  Herrick,  M.  D.,  Professor  of  the 
Practice  of  Medicine,  Rush  Medical  College.     Octavo  of  815  pages,  illust. 

Diseases  of  the  Heart 

By  Prof.  Dr.  Th.  von  Jurgense.x,  of  Tubingen  ;  Prof.  Dr.  L.  Krehl, 
of  Greifswald  ;  and  Prof.  Dr.  L.  von  Schrotter,  of  Vienna.  The  entire 
volume  edited,  with  additions,  by  George  Dock,  M.  D.,  Professor  of  Theory 
and  Practice  of  Medicine  and  Clinical  Medicine,  Tulane  University  of 
Louisiana.     Octavo  of  848  pages,  fully  illustrated. 

SOLD  SEPARATELY— PER  VOLUME:   CLOTH,  $5.00  NET;   HALF   MOROCCO,    $6.00  NET 

Goepp's  State    Board     Questions 

State  Board  Questions  and  Answers. — By  R.  Max  Goepp,  M.  D., 

Professor  of  Clinical   Medicine,  Philadelphia  Polyclinic.     Octavo  of  684 

pages.  Cloth,  S4.00  net;  Half  Morocco,  $5.50  net. 

Pennsylvania  Medical  Journal 

"  Nothing  has  been  printed  which  is  so  admirably  adapted  as  a  guide  and  self-quiz  for  those 
intending  to  take  State  Board  Examinations." 


12  SAUNDERS'     BOOKS    ON 

Amy's 
Principles  qf  Pharmacy 

Principles  of  Pharmacy.     By  Henry   V.   Arny,    Ph.  G.,   Ph.  D., 

Professor  of  Pharmacy  at  the  Cleveland  School  of  Pharmacy.     Octavo 
of  1 175  pages,  with  246  illustrations.     Cloth,  $5.00  net. 

RECENTLY  ISSUED 

Professor  Arny  divides  his  subject  into  seven  parts  :  The  first  part  deals  with 
pharmaceutic  processes,  a  striking  feature  being  the  clear  discussion  of  the  arith- 
metic of  pharmacy  ;  the  second  part  deals  with  galenic  preparations  of  the  Phar- 
macopeia and  those  unofficial  preparations  of  proved  value  ;  the  third  part  deals 
with  the  inorganic  chemicals  ;  the  fourth  part  discusses  the  organic  chemicals  ;  the 
fifth  part  is  devoted  to  chemical  testing,  presenting  a  systematic  grouping  of  all 
the  tests  of  the  Pharmacopeia — a  feature  not  found  in  any  other  book  ;  the  sixth 
part  discusses  the  prescription  ;  the  seventh  part  is  devoted  to  laboratory  work. 

George  Reimann,   Ph.  G.,   Secretary  of  the  New  York  State  Board  of  Pharmacy. 

"  I  would  say  that  the  book  is  certainly  a  great  help  to  the  student,  and  I  think  it  ought  to 
be  in  the  hands  of  every  person  who  is  contemplating  the  study  of  pharmacy." 

Stevens'  Therapeutics 
and   Materia   Medica 

A  Text=Book  of  Modern  Materia  Medica  and  Therapeutics.     By 

A.  A.  Stevens,  A.  M.,  M.  D.,  Lecturer  on  Physical  Diagnosis  in  the 
University  of  Pennsylvania.     Octavo  of  675  pages.     Cloth,  $3.50  net. 

RECENTLY  ISSUED— THE  NEW  (5th)  EDITION 

Dr.  Stevens'  Therapeutics  is  one  of  the  most  successful  works  on  the  subject 
ever  published.  In  this  new  edition  the  work  has  undergone  a  very  thorough 
revision,  and  now  represents  the  very  latest  advances  in  therapeutics  and  materia 
medica. 

The  Medical  Record,  New  York 

"Among  the  numerous  treatises  on  this  most  important  branch  of  medical  practice,  this  by 
Dr.  Stevens  has  ranked  with  the  best,  and  the  new  edition  preserves  its  reputation  as  one  of  the 
most  authoritative  works  on  therapeutics  and  materia  medica." 


MATERIA    MEDICA.  13 


Sollmann's  Pharmacology 

Including  Therapeutics,  Materia  Medica.  Pharmacy, 
Prescription-writing',  Toxicology,  etc. 


A  Text=Book  of  Pharmacology.  By  Torald  Sollmann,  M.  D., 
Professor  of  Pharmacology  and  Materia  Medica,  Medical  Department 
of  Western  Reserve  University,  Clevjland,  Ohio.  Handsome  octavo 
volume  of  1070  pages,  fully  illustrated.     Cloth,  $4.00  net. 

THE    NEW   (2d)   EDITION 

Because  of  the  radical  alterations  which  have  been  made  in  the  new  (1905) 
Pharmacopeia,  it  was  found  necessary  to  reset  this  book  entirely.  The  author 
bases  the  study  of  therapeutics  on  a  systematic  knowledge  of  the  nature  and 
properties  of  drugs,  and  thus  brings  out  forcibly  the  intimate  relation  between 
pharmacology  and  practical  medicine. 

J.  F.  Fotheringhamc  M.  D. 

Prof,  of  Therapeutics  and  Theory  and  Practice  of  Prescribing   Trinity  Med.  College,  Toronto. 
"The  work  certainly  occupies  ground  not  covered  in  so  concise,  useful,  and  scientific  a 
manner  by  any  other  text  I  have  read  on  the  subjects  embraced." 

Butler's   Materia   Medica 

Therapeutics,  and  Pharmacology 


A  Text-Book  of  Materia  Medica,  Therapeutics,  and  Pharmacology. 

By  George  F.  Butler,  Ph.  G.,  M.  D.,  Professor  and  Head  of  the 
Department  of  Therapeutics  and  Professor  of  Preventive  and  Clinical 
Medicine,  Chicago  College  of  Medicine  and  Surgery,  Medical  Depart- 
ment Valparaiso  University.  Octavo  of  702  pages,  illustrated.  Cloth, 
#4.00  net ;  Half  Morocco,  $5.50  net. 

THE    NEW    (6th)    EDITION 

For  this  sixth  edition  Dr.  Butler  has  entirely  remodeled  his  work,  a  great  part 
having  been  rewritten.  All  obsolete  matter  has  been  eliminated,  and  special  atten- 
tion has  been  given  to  the  toxicologic  and  therapeutic  effects  of  the  newer  com- 
pounds. The  classification  adopted  is  a  practical  one,  aiding  the  student  in  grasp- 
ing the  subject,  and  the  practitioner  in  finding  the  information  sought. 

Medical  Record,  New  York 

"  Nothing  has  been  omitted  by  the  author  which,  in  his  judgment,  would  add  to  the  com- 
pleteness of  the  text,  and  the  student  or  general  reader  is  given  the  benefit  of  latest  advices 
bearing  upon  the  value  of  drugs  and  remedies  considered." 


14  SAUNDERS'    BOOKS    ON 

GET  A  •  THE  NEW 

THE  BEST  i\  111  S  F  1  C  Ct  11  STANDARD 

Illustrated    Dictionary 


Recently  Issued — The  New  (5th)  Edition 

The  American  Illustrated  Medical  Dictionary — By  W.  A.  New- 
man Dorland,  M.  D.,  Editor  of  "The  American  Pocket  Medical  Dic- 
tionary." Large  octavo  of  876  pages,  bound  in  full  flexible  leather. 
Price,  $4.50  net;  with  thumb  index,  £5.00  net. 

A  KEY  TO  MEDICAL  LITERATURE— WITH  2000  NEW  TERMS 

Howard  A.  Kelly.M.D .,  Professor  of  Gynecologic  Surgery,  fohns  Hopkins  University. 

"  Dr.  Dorland's  dictionary  is  admirable.  It  is  so  well  gotten  up  and  of  such  convenient 
size.     No  errors  have  been  found  in  my  use  of  it." 


Thornton's  Dose=Book.  Ne^uthf Edition 

Dose-Book  and  Manual  of  Prescription-Writing.  ByE.  Q.  Thornton,  M.D., 
Assistant  Professor  of  Materia  Medica,  Jefferson  Medical  College,  Philadelphia.  Post- 
octavo,  410  pages,  illustrated.      Flexible  leather,  $2.00  net. 

"  I  will  be  able  to  make  considerable  use  of  that  part  of  its  contents  relating  to  the  correct 
terminology  as  used  in  prescription-writing,  and  it  will  afford  me  much  pleasure  to  recom- 
mend the  book  to  my  classes,  who  often  fail  to  find  this  information  in  their  other  text- 
books."— C.  H.  MILLER,  M.D.,  Professor  of  Pharmacology,  Northwestern  University  Medi- 
cal School. 

.    .  Just  Ready 

Lusk    OII    Nutrition  New   ^2d)   Edition 

Elements  of  the  Science  of  Nutrition.  By  Graham  Lusk,  Ph.  D.,  Professor 
of  Physiology  in  Cornell  University  Medical  School.  Octavo  of  402  pages.  Cloth, 
$3.00  net. 

"  I  shall  recommend  it  highly.  It  is  a  comfort  to  have  such  a  discussion  of  the  subject." 
— LEWELLYS  F.  Barker,  M.  D.,  fohns  Hopkins  University. 

Camac's  "Epoch-making  Contributions" 

Epoch-making  Contributions  in  Medicine  and  Surgery.  Collected  and 
arranged  by  C.  N.  B.  Camac,  M.  D.,  of  New  York  City.  Octavo  of  450  pages,  illus- 
trated.    Artistically  bound,  $4.00  net. 

"  Dr.  Camac  has  provided  us  with  a  most  interesting  aggregation  of  classical  essays# 
We  hope  that  members  of  the  profession  will  show  their  appreciation  of  his  endeavors." — 
Therapeutic  Gazette. 


PRACTICE,    MATERIA   MEDIC  A,   Etc.  15 


The  American  Pocket  Medical  Dictionary  New  (6th)  Edition 

The  American  Pocket  Medical  Dictionary.  Edited  by  W.  A.  Newman  Dor- 
LAND,  M.  D.,  Assistant  Obstetrician  to  the  Hospital  of  the  University  of  Pennsylvania. 
598  pages.      Flexible  leather,  with  gold  edges,  $1.00  net ;  with  thumb  index,  $1.25  net". 

Pusey  and  Caldwell  on  X-Rays  Second  Edition 

The  Practical  Application  of  the  Rontgen  Rays  in  Therapeutics  and 
Diagnosis.  By  William  Allen  Pusey,  A.  M.,  M.  D.,  Professor  of  Dermatology  in 
the  University  of  Illinois ;  and  Eugene  W.  Caldwell,  B.  S.,  Director  of  the  Edward 
N.  Gibbs  X-Ray  Memorial  Laboratory  of  the  University  and  Bellevue  Hospital  Medical 
College,  New  York.  Octavo  of  625  pages,  with  200  illustrations.  Cloth,  #5.00  net; 
Half  Morocco,  #6.50  net. 

Cohen   and   Eshner's   Diagnosis.      Second  Revised  Edition 

Essentials  of  Diagnosis.  By  S.  Solis-Cohen,  M.  D.,  Senior  Assistant  Professor 
in  Clinical  Medicine,  Jefferson  Medical  College,  Phila.  ;  and  A.  A.  Eshner,  M.  D., 
Professor  of  Clinical  Medicine,  Philadelphia  Polyclinic.  Post-octavo,  3S2  pages  ;  55 
illustrations.      Cloth,  $1. 00  net.     In  Saunders'  Question- Compend  Series. 

Morris'  Materia  Medica  and  Therapeutics.  New  (7th)  Edition 

Essentials  of  Materia  Medica,  Therapeutics,  and  Prescription-Writing. 
By  Henry  Morris,  M.  D.,  late  Demonstrator  of  Therapeutics,  Jefferson  Medical 
College,  Phila.  Revised  by  W.  A.  Bastedo,  M.  D.,  Instructor  in  Materia  Medica  and 
Pharmacology  at  Columbia  University.   1 2mo,  300 pages.    Cloth,  $1.00  net.  In  Saunders' 

Question-  Compend  Series. 

Williams'  Practice  of  Medicine 

Essentials  of  the  Practice  of  Medicine.  By  W.  R.  Williams,  M.D., 
formerly  Instructor  in  Medicine  and  Lecturer  on  Hygiene,  Cornell  University  ;  and 
Tutor  in  Therapeutics,  Columbia  University,  N.  Y.  l2mo  of  456  pages,  illustrated. 
In  Saunders^  Question- Compend  Series.     Double  number,  $1.75  net. 

Todd's  Clinical  Diagnosis 

A  Manual  of  Clinical  Diagnosis.  By  James  Campbell  Todd,  M.  D.,  Associate 
Professor  of  Pathology,  Denver  and  Gross' College  of  Medicine.  i2moof3l9  pages, 
with  131  text-illustrations  and  10  colored  plates.      Flexible  leather,  $2.00  net. 

Bridge  on  Tuberculosis 

Tuberculosis.  By  Norman  Bridge,  A.  M.,  M.  D.,  Emeritus  Professor  of  Medicine 
in  Rush  Medical  College.     i2mo  of  302  pages,  illustrated.     Cloth,  $1.50  net. 

Boston's  Clinical  Diagnosis  Second  Edition 

Clinical  Diagnosis.  By  L.  Napoleon  Boston,  M.  D.,  Adjunct  Professor  of  Medi- 
cine and  Director  of  the  Clinical  Laboratories,  Medico-Chirurgical  College,  Philadel- 
phia.    Octavo  of  563  pages,  with  330  illustrations,  many  in  colors.     Cloth,  $4.00  net. 

Arnold's  Medical  Diet  Charts 

Medical  Diet  Charts.  Prepared  by  H.  D.  Arnold,  M.D.,  Professor  of  Clinical 
Medicine,  Tuft's  Medical  College,  Boston.  Single  charts,  5  cents;  50  charts,  $2.00  net; 
500  charts,  $iS.oo  net;   1000  charts,  $30.00  net. 

Mathews'  How  to  Succceed  in  Practice 

How  to  Succeed  in  the  Practice  of  Medicine.  By  Joseph  M.  Mathews, 
M.  D.,  LL.D.,  President  American  Medical  Association,  1898-99.  urao  of  215  pages, 
illustrated.     Cloth,  $1.50  net. 


1 6  SAUNDERS*    BOOKS   ON  PRACTICE,  Etc. 

Jakob  and  Eshner's  Internal  Medicine  and  Diagnosis 

Atlas  and  Epitome  of  Internal  Medicine  and  Clinical  Diagnosis.  By  Dr. 
Chr.  Jakob,  of  Erlangen.  Edited,  with  additions,  by  A.  A.  Eshner,  M.  D.,  Pro- 
fessor of  Ginical  Medicine,  Philadelphia  Polyclinic.  With  182  colored  figures  on 
68  plates,  64  text-illustrations,  259  pages  of  text.  Cloth,  $3.00  net.  In  Sounders' 
Hand-Atlas  Series. 

LockWood's  Practice  of  Medicine.  ■JSStLfBi, 

A  Manual  of  the  Practice  of  Medicine.  By  Geo.  Roe  Lockwood,  M.  D., 
Attending  Physician  to  the  Bellevue  Hospital,  New  York  City.  Octavo,  847  pages, 
with  79  illustrations  in  the  text  and  22  full-page  plates.      Cloth,  §4.00  net. 

Barton  and  Wells'  Medical  Thesaurus 

A  Thesaurus  of  Medical  Words  and  Phrases.  By  W.  M.  Barton,  M.  D.,  and 
W.  A.  Wells.  M.  D.,  of  Georgetown  University,  Washington,  D.  C.  l2mo  of  535 
pages.     Flexible  leather,  S2. 50  net;  thumb  indexed,  $3.00  net. 

Jelliffe's  Pharmacognosy 

An  Introduction  to  Pharmacognosy.  By  Smith  Ely  Jelliffe,  Ph.  D.,  M.  D., 
of  Columbia  University.     Octavo,  illustrated.     Cloth,  S2.50  net. 

Stevens'  Practice   of   Medicine  New  (8th)  Edition 

A  Manual  of  the  Practice  of  Medicine.     By  A.  A.  Stevens,  A.  M.,  M.  D., 

Professor   of    Pathology,    Woman's    Medical    College,    Phila.  Specially   intended  for 

students  preparing  for  graduation  and  hospital  examinations.  Post-octavo,  556  pages, 
illustrated.     Flexible  leather,  S2.50   net. 

Rolleston  on  the  Liver 

Diseases  of  the  Livfr,  Gall-bladder,  and  Bile-ducts.  By  H.  D.  Rolles- 
ton, M.  D.  (Cantab),  F.  R.  C.  P..  Physician  to  St.  George's  Hospital,  London,  Eng- 
land.    Octavo  of  794  pages,  illustrated.      Cloth,  $6.00  net. 

Saunders'  Pocket  Formulary  New  (9th)  Edition 

Saunders'  Pocket  Medical  Formulary.  By  William  M.  Powell,  M.  D. 
Containing  1S31  formulas  from  the  best-known  authorities.  With  an  Appendix  con- 
taining Posologic  Table,  Formulas  and  Doses  for  Hvpodermic  Medication,  Poisons  and 
their  Antidotes,  Diameters  of  the  Female  Pelvis  and  Fetal  Head,  Obstetrical  Table, 
Diet-list,  Materials  and  Drugs  used  in  Antiseptic  Surgery,  Treatment  of  Asphyxia  from 
Drowning,  Surgical  Remembrancer,  Tables  of  Incompatibles,  Eruptive  Fevers,  etc., 
etc.     In  flexible  leather,  with  side  index,  wallet,  and  flap,  Si-75  net. 

Gould  and  Pyle's  Curiosities  of  Medicine 

Anomalies  and  Curiosities  of  Medicine.  By  George  M.  Gould,  M.  D.,  and 
Walter  L.  Pyle.  M.  D.  Octavo  of  968  pages,  295  engravings,  and  12  full-page  plates. 
Cloth,  S3.00  net;  Half  Morocco,  $4.50  net. 

Hatcher  and  Sollmann's  Materia  Medica 

A  Text-Book  OF  Materia  Medica  :  including  Laboratory  Exercises  in  the  Histo- 
logic and  Chemic  Examination  of  Drugs.  By  Robert  A.  Hatcher,  Ph.  G.,  M.  D., 
and  Torald  SOLLMANN,  M.  D.     i2mo  of  411  pages.     Flexible  leather,  32.00  net. 

Eichhorst's  Practice  of  Medicine 

A  Text-Book  of  the  Practice  of  Medicine.  By  Dr.  H.  Eichhorst,  Univer- 
sity of  Zurich.  Edited  by  A.  A.  ESHNER,  M.  D.  Two  octavos  of  600  pages  each,  illus- 
trated.    Per  set:  Cloth,  S6.00  net. 


.    ; 


*tf  i  o 


&M 


NOV  19 


^: 


(947 


